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DNA repair

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur. This can eventually lead to malignant tumors, or cancer as per the two-hit hypothesis.

The rate of DNA repair is dependent on many factors, including the cell type, the age of the cell, and the extracellular environment. A cell that has accumulated a large amount of DNA damage, or one that no longer effectively repairs damage incurred to its DNA, can enter one of three possible states:
 * 1) an irreversible state of dormancy, known as senescence
 * 2) cell suicide, also known as apoptosis or programmed cell death
 * 3) unregulated cell division, which can lead to the formation of a tumor that is cancerous

The DNA repair ability of a cell is vital to the integrity of its genome and thus to the normal functionality of that organism. Many genes that were initially shown to influence life span have turned out to be involved in DNA damage repair and protection.

The 2015 Nobel Prize in Chemistry was awarded to Tomas Lindahl, Paul Modrich, and Aziz Sancar for their work on the molecular mechanisms of DNA repair processes.

DNA damage
DNA damage, due to environmental factors and normal metabolic processes inside the cell, occurs at a rate of 10,000 to 1,000,000 molecular lesions per cell per day. While this constitutes at most only 0.0003125% of the human genome's approximately 3.2 billion bases, unrepaired lesions in critical genes (such as tumor suppressor genes) can impede a cell's ability to carry out its function and appreciably increase the likelihood of tumor formation and contribute to tumor heterogeneity.

The vast majority of DNA damage affects the primary structure of the double helix; that is, the bases themselves are chemically modified. These modifications can in turn disrupt the molecules' regular helical structure by introducing non-native chemical bonds or bulky adducts that do not fit in the standard double helix. Unlike proteins and RNA, DNA usually lacks tertiary structure and therefore damage or disturbance does not occur at that level. DNA is, however, supercoiled and wound around "packaging" proteins called histones (in eukaryotes), and both superstructures are vulnerable to the effects of DNA damage.

Types
There are several types of damage to DNA due to endogenous cellular processes:
 * 1) oxidation of bases [e.g. 8-oxo-7,8-dihydroguanine (8-oxoG)] and generation of DNA strand interruptions from reactive oxygen species,
 * 2) alkylation of bases (usually methylation), such as formation of 7-methylguanosine, 1-methyladenine, 6-O-Methylguanine
 * 3) hydrolysis of bases, such as deamination, depurination, and depyrimidination.
 * 4) "bulky adduct formation" (e.g., benzo[a]pyrene diol epoxide-dG adduct, aristolactam I-dA adduct)
 * 5) mismatch of bases, due to errors in DNA replication, in which the wrong DNA base is stitched into place in a newly forming DNA strand, or a DNA base is skipped over or mistakenly inserted.
 * 6) Monoadduct damage cause by change in single nitrogenous base of DNA
 * 7) Di adduct damage

Damage caused by exogenous agents comes in many forms. Some examples are:
 * 1) UV-B light causes crosslinking between adjacent cytosine and thymine bases creating pyrimidine dimers. This is called direct DNA damage.
 * 2) UV-A light creates mostly free radicals. The damage caused by free radicals is called indirect DNA damage.
 * 3) Ionizing radiation such as that created by radioactive decay or in cosmic rays causes breaks in DNA strands.  Intermediate-level ionizing radiation may induce irreparable DNA damage (leading to replicational and transcriptional errors needed for neoplasia or may trigger viral interactions) leading to pre-mature aging and cancer.
 * 4) Thermal disruption at elevated temperature increases the rate of depurination (loss of purine bases from the DNA backbone) and single-strand breaks. For example, hydrolytic depurination is seen in the thermophilic bacteria, which grow in hot springs at 40–80 °C. The rate of depurination (300 purine residues per genome per generation) is too high in these species to be repaired by normal repair machinery, hence a possibility of an adaptive response cannot be ruled out.
 * 5) Industrial chemicals such as vinyl chloride and hydrogen peroxide, and environmental chemicals such as polycyclic aromatic hydrocarbons found in smoke, soot and tar create a huge diversity of DNA adducts- ethanoates, oxidized bases, alkylated phosphodiesters and crosslinking of DNA, just to name a few.

UV damage, alkylation/methylation, X-ray damage and oxidative damage are examples of induced damage. Spontaneous damage can include the loss of a base, deamination, sugar ring puckering and tautomeric shift. Constitutive (spontaneous) DNA damage caused by endogenous oxidants can be detected as a low level of histone H2AX phosphorylation in untreated cells.

Nuclear versus mitochondrial
In human cells, and eukaryotic cells in general, DNA is found in two cellular locations – inside the nucleus and inside the mitochondria. Nuclear DNA (n-DNA) exists as chromatin during non-replicative stages of the cell cycle and is condensed into aggregate structures known as chromosomes during cell division. In either state the DNA is highly compacted and wound up around bead-like proteins called histones. Whenever a cell needs to express the genetic information encoded in its n-DNA the required chromosomal region is unraveled, genes located therein are expressed, and then the region is condensed back to its resting conformation. Mitochondrial DNA (mtDNA) is located inside mitochondria organelles, exists in multiple copies, and is also tightly associated with a number of proteins to form a complex known as the nucleoid. Inside mitochondria, reactive oxygen species (ROS), or free radicals, byproducts of the constant production of adenosine triphosphate (ATP) via oxidative phosphorylation, create a highly oxidative environment that is known to damage mtDNA. A critical enzyme in counteracting the toxicity of these species is superoxide dismutase, which is present in both the mitochondria and cytoplasm of eukaryotic cells.

Senescence and apoptosis
Senescence, an irreversible process in which the cell no longer divides, is a protective response to the shortening of the chromosome ends, called telomeres. The telomeres are long regions of repetitive noncoding DNA that cap chromosomes and undergo partial degradation each time a cell undergoes division (see Hayflick limit). In contrast, quiescence is a reversible state of cellular dormancy that is unrelated to genome damage (see cell cycle). Senescence in cells may serve as a functional alternative to apoptosis in cases where the physical presence of a cell for spatial reasons is required by the organism, which serves as a "last resort" mechanism to prevent a cell with damaged DNA from replicating inappropriately in the absence of pro-growth cellular signaling. Unregulated cell division can lead to the formation of a tumor (see cancer), which is potentially lethal to an organism. Therefore, the induction of senescence and apoptosis is considered to be part of a strategy of protection against cancer.

Mutation
It is important to distinguish between DNA damage and mutation, the two major types of error in DNA. DNA damage and mutation are fundamentally different. Damage results in physical abnormalities in the DNA, such as single- and double-strand breaks, 8-hydroxydeoxyguanosine residues, and polycyclic aromatic hydrocarbon adducts. DNA damage can be recognized by enzymes, and thus can be correctly repaired if redundant information, such as the undamaged sequence in the complementary DNA strand or in a homologous chromosome, is available for copying. If a cell retains DNA damage, transcription of a gene can be prevented, and thus translation into a protein will also be blocked. Replication may also be blocked or the cell may die.

In contrast to DNA damage, a mutation is a change in the base sequence of the DNA. A mutation cannot be recognized by enzymes once the base change is present in both DNA strands, and thus a mutation cannot be repaired. At the cellular level, mutations can cause alterations in protein function and regulation. Mutations are replicated when the cell replicates. In a population of cells, mutant cells will increase or decrease in frequency according to the effects of the mutation on the ability of the cell to survive and reproduce.

Although distinctly different from each other, DNA damage and mutation are related because DNA damage often causes errors of DNA synthesis during replication or repair; these errors are a major source of mutation.

Given these properties of DNA damage and mutation, it can be seen that DNA damage is a special problem in non-dividing or slowly-dividing cells, where unrepaired damage will tend to accumulate over time. On the other hand, in rapidly dividing cells, unrepaired DNA damage that does not kill the cell by blocking replication will tend to cause replication errors and thus mutation. The great majority of mutations that are not neutral in their effect are deleterious to a cell's survival. Thus, in a population of cells composing a tissue with replicating cells, mutant cells will tend to be lost. However, infrequent mutations that provide a survival advantage will tend to clonally expand at the expense of neighboring cells in the tissue. This advantage to the cell is disadvantageous to the whole organism because such mutant cells can give rise to cancer. Thus, DNA damage in frequently dividing cells, because it gives rise to mutations, is a prominent cause of cancer. In contrast, DNA damage in infrequently-dividing cells is likely a prominent cause of aging.

Mechanisms
Cells cannot function if DNA damage corrupts the integrity and accessibility of essential information in the genome (but cells remain superficially functional when non-essential genes are missing or damaged). Depending on the type of damage inflicted on the DNA's double helical structure, a variety of repair strategies have evolved to restore lost information. If possible, cells use the unmodified complementary strand of the DNA or the sister chromatid as a template to recover the original information. Without access to a template, cells use an error-prone recovery mechanism known as translesion synthesis as a last resort.

Damage to DNA alters the spatial configuration of the helix, and such alterations can be detected by the cell. Once damage is localized, specific DNA repair molecules bind at or near the site of damage, inducing other molecules to bind and form a complex that enables the actual repair to take place.

Direct reversal
Cells are known to eliminate three types of damage to their DNA by chemically reversing it. These mechanisms do not require a template, since the types of damage they counteract can occur in only one of the four bases. Such direct reversal mechanisms are specific to the type of damage incurred and do not involve breakage of the phosphodiester backbone. The formation of pyrimidine dimers upon irradiation with UV light results in an abnormal covalent bond between adjacent pyrimidine bases. The photoreactivation process directly reverses this damage by the action of the enzyme photolyase, whose activation is obligately dependent on energy absorbed from blue/UV light (300–500 nm wavelength) to promote catalysis. Photolyase, an old enzyme present in bacteria, fungi, and most animals no longer functions in humans, who instead use nucleotide excision repair to repair damage from UV irradiation. Another type of damage, methylation of guanine bases, is directly reversed by the enzyme methyl guanine methyl transferase (MGMT), the bacterial equivalent of which is called ogt. This is an expensive process because each MGMT molecule can be used only once; that is, the reaction is stoichiometric rather than catalytic. A generalized response to methylating agents in bacteria is known as the adaptive response and confers a level of resistance to alkylating agents upon sustained exposure by upregulation of alkylation repair enzymes. The third type of DNA damage reversed by cells is certain methylation of the bases cytosine and adenine.

Single-strand damage
When only one of the two strands of a double helix has a defect, the other strand can be used as a template to guide the correction of the damaged strand. In order to repair damage to one of the two paired molecules of DNA, there exist a number of excision repair mechanisms that remove the damaged nucleotide and replace it with an undamaged nucleotide complementary to that found in the undamaged DNA strand.
 * 1) Base excision repair (BER): damaged single bases or nucleotides are most commonly repaired by removing the base or the nucleotide involved and then inserting the correct base or nucleotide. In base excision repair, a glycosylase enzyme removes the damaged base from the DNA by cleaving the bond between the base and the deoxyribose. These enzymes remove a single base to create an apurinic or apyrimidinic site (AP site). Enzymes called AP endonucleases nick the damaged DNA backbone at the AP site. DNA polymerase then removes the damaged region using its 5' to 3'  exonuclease activity and correctly synthesizes the new strand using the complementary strand as a template. The gap is then sealed by enzyme DNA ligase.
 * 2) Nucleotide excision repair (NER): bulky, helix-distorting damage, such as pyrimidine dimerization caused by UV light is usually repaired by a three-step process. First the damage is recognized, then 12-24 nucleotide-long strands of DNA are removed both upstream and downstream of the damage site by endonucleases, and the removed DNA region is then resynthesized. NER is a highly evolutionarily conserved repair mechanism and is used in nearly all eukaryotic and prokaryotic cells. In prokaryotes, NER is mediated by Uvr proteins. In eukaryotes, many more proteins are involved, although the general strategy is the same.
 * 3) Mismatch repair systems are present in essentially all cells to correct errors that are not corrected by proofreading. These systems consist of at least two proteins. One detects the mismatch, and the other recruits an endonuclease that cleaves the newly synthesized DNA strand close to the region of damage. In E. coli , the proteins involved are the Mut class proteins: MutS, MutL, and MutH. In most Eukaryotes, the analog for MutS is MSH and the analog for MutL is MLH. MutH is only present in bacteria. This is followed by removal of damaged region by an exonuclease, resynthesis by DNA polymerase, and nick sealing by DNA ligase.

Double-strand breaks

Double-strand breaks, in which both strands in the double helix are severed, are particularly hazardous to the cell because they can lead to genome rearrangements. In fact, when a double-strand break is accompanied by a cross-linkage joining the two strands at the same point, neither strand can be used as a template for the repair mechanisms, so that the cell will not be able to complete mitosis when it next divides, and will either die or, in rare cases, undergo a mutation. Three mechanisms exist to repair double-strand breaks (DSBs): non-homologous end joining (NHEJ), microhomology-mediated end joining (MMEJ), and homologous recombination (HR):

 * 1) In NHEJ, DNA Ligase IV, a specialized DNA ligase that forms a complex with the cofactor XRCC4, directly joins the two ends. To guide accurate repair, NHEJ relies on short homologous sequences called microhomologies present on the single-stranded tails of the DNA ends to be joined. If these overhangs are compatible, repair is usually accurate.  NHEJ can also introduce mutations during repair. Loss of damaged nucleotides at the break site can lead to deletions, and joining of nonmatching termini forms insertions or translocations. NHEJ is especially important before the cell has replicated its DNA, since there is no template available for repair by homologous recombination. There are "backup" NHEJ pathways in higher eukaryotes. Besides its role as a genome caretaker, NHEJ is required for joining hairpin-capped double-strand breaks induced during V(D)J recombination, the process that generates diversity in B-cell and T-cell receptors in the vertebrate immune system.
 * 2) MMEJ starts with short-range end resection by MRE11 nuclease on either side of a double-strand break to reveal microhomology regions.  In further steps, Poly (ADP-ribose) polymerase 1 (PARP1) is required and may be an early step in MMEJ.  There is pairing of microhomology regions followed by recruitment of flap structure-specific endonuclease 1 (FEN1) to remove overhanging flaps.  This is followed by recruitment of XRCC1–LIG3 to the site for ligating the DNA ends, leading to an intact DNA. MMEJ is always accompanied by a deletion, so that MMEJ is a mutagenic pathway for DNA repair.
 * 3) HR requires the presence of an identical or nearly identical sequence to be used as a template for repair of the break. The enzymatic machinery responsible for this repair process is nearly identical to the machinery responsible for chromosomal crossover during meiosis. This pathway allows a damaged chromosome to be repaired using a sister chromatid (available in G2 after DNA replication) or a homologous chromosome as a template. DSBs caused by the replication machinery attempting to synthesize across a single-strand break or unrepaired lesion cause collapse of the replication fork and are typically repaired by recombination.

In an in vitro system, MMEJ occurred in mammalian cells at the levels of 10–20% of HR when both HR and NHEJ mechanisms were also available.

The extremophile Deinococcus radiodurans has a remarkable ability to survive DNA damage from ionizing radiation and other sources. At least two copies of the genome, with random DNA breaks, can form DNA fragments through annealing. Partially overlapping fragments are then used for synthesis of homologous regions through a moving D-loop that can continue extension until complementary partner strands are found. In the final step, there is crossover by means of RecA-dependent homologous recombination.

Topoisomerases introduce both single- and double-strand breaks in the course of changing the DNA's state of supercoiling, which is especially common in regions near an open replication fork. Such breaks are not considered DNA damage because they are a natural intermediate in the topoisomerase biochemical mechanism and are immediately repaired by the enzymes that created them.

Another type of DNA double-strand breaks originates from the DNA heat-sensitive or heat-labile sites. These DNA sites are not initial DSBs. However, they convert to DSB after treating with elevated temperature. Ionizing irradiation can induces a highly complex form of DNA damage as clustered damage. It consists of different types of DNA lesions in various locations of the DNA helix. Some of these closely located lesions can probably convert to DSB by exposure to high temperatures. But the exact nature of these lesions and their interactions is not yet known

Translesion synthesis
Translesion synthesis (TLS) is a DNA damage tolerance process that allows the DNA replication machinery to replicate past DNA lesions such as thymine dimers or AP sites. It involves switching out regular DNA polymerases for specialized translesion polymerases (i.e. DNA polymerase IV or V, from the Y Polymerase family), often with larger active sites that can facilitate the insertion of bases opposite damaged nucleotides. The polymerase switching is thought to be mediated by, among other factors, the post-translational modification of the replication processivity factor PCNA. Translesion synthesis polymerases often have low fidelity (high propensity to insert wrong bases) on undamaged templates relative to regular polymerases. However, many are extremely efficient at inserting correct bases opposite specific types of damage. For example, Pol η mediates error-free bypass of lesions induced by UV irradiation, whereas Pol ι introduces mutations at these sites. Pol η is known to add the first adenine across the T^T photodimer using Watson-Crick base pairing and the second adenine will be added in its syn conformation using Hoogsteen base pairing. From a cellular perspective, risking the introduction of point mutations during translesion synthesis may be preferable to resorting to more drastic mechanisms of DNA repair, which may cause gross chromosomal aberrations or cell death. In short, the process involves specialized polymerases either bypassing or repairing lesions at locations of stalled DNA replication. For example, Human DNA polymerase eta can bypass complex DNA lesions like guanine-thymine intra-strand crosslink, G[8,5-Me]T, although it can cause targeted and semi-targeted mutations. Paromita Raychaudhury and Ashis Basu studied the toxicity and mutagenesis of the same lesion in Escherichia coli by replicating a G[8,5-Me]T-modified plasmid in E. coli with specific DNA polymerase knockouts. Viability was very low in a strain lacking pol II, pol IV, and pol V, the three SOS-inducible DNA polymerases, indicating that translesion synthesis is conducted primarily by these specialized DNA polymerases. A bypass platform is provided to these polymerases by Proliferating cell nuclear antigen (PCNA). Under normal circumstances, PCNA bound to polymerases replicates the DNA. At a site of lesion, PCNA is ubiquitinated, or modified, by the RAD6/RAD18 proteins to provide a platform for the specialized polymerases to bypass the lesion and resume DNA replication. After translesion synthesis, extension is required. This extension can be carried out by a replicative polymerase if the TLS is error-free, as in the case of Pol η, yet if TLS results in a mismatch, a specialized polymerase is needed to extend it; Pol ζ. Pol ζ is unique in that it can extend terminal mismatches, whereas more processive polymerases cannot. So when a lesion is encountered, the replication fork will stall, PCNA will switch from a processive polymerase to a TLS polymerase such as Pol ι to fix the lesion, then PCNA may switch to Pol ζ to extend the mismatch, and last PCNA will switch to the processive polymerase to continue replication.

Global response to DNA damage
Cells exposed to ionizing radiation, ultraviolet light or chemicals are prone to acquire multiple sites of bulky DNA lesions and double-strand breaks. Moreover, DNA damaging agents can damage other biomolecules such as proteins, carbohydrates, lipids, and RNA. The accumulation of damage, to be specific, double-strand breaks or adducts stalling the replication forks, are among known stimulation signals for a global response to DNA damage. The global response to damage is an act directed toward the cells' own preservation and triggers multiple pathways of macromolecular repair, lesion bypass, tolerance, or apoptosis. The common features of global response are induction of multiple genes, cell cycle arrest, and inhibition of cell division.

Initial steps
The packaging of eukaryotic DNA into chromatin presents a barrier to all DNA-based processes that require recruitment of enzymes to their sites of action. To allow DNA repair, the chromatin must be remodeled. In eukaryotes, ATP dependent chromatin remodeling complexes and histone-modifying enzymes are two predominant factors employed to accomplish this remodeling process.

Chromatin relaxation occurs rapidly at the site of a DNA damage. In one of the earliest steps, the stress-activated protein kinase, c-Jun N-terminal kinase (JNK), phosphorylates SIRT6 on serine 10 in response to double-strand breaks or other DNA damage. This post-translational modification facilitates the mobilization of SIRT6 to DNA damage sites, and is required for efficient recruitment of poly (ADP-ribose) polymerase 1 (PARP1) to DNA break sites and for efficient repair of DSBs. PARP1 protein starts to appear at DNA damage sites in less than a second, with half maximum accumulation within 1.6 seconds after the damage occurs. PARP1 synthesizes polymeric adenosine diphosphate ribose (poly (ADP-ribose) or PAR) chains on itself. Next the chromatin remodeler ALC1 quickly attaches to the product of PARP1 action, a poly-ADP ribose chain, and ALC1 completes arrival at the DNA damage within 10 seconds of the occurrence of the damage. About half of the maximum chromatin relaxation, presumably due to action of ALC1, occurs by 10 seconds. This then allows recruitment of the DNA repair enzyme MRE11, to initiate DNA repair, within 13 seconds.

γH2AX, the phosphorylated form of H2AX is also involved in the early steps leading to chromatin decondensation after DNA double-strand breaks. The histone variant H2AX constitutes about 10% of the H2A histones in human chromatin. γH2AX (H2AX phosphorylated on serine 139) can be detected as soon as 20 seconds after irradiation of cells (with DNA double-strand break formation), and half maximum accumulation of γH2AX occurs in one minute. The extent of chromatin with phosphorylated γH2AX is about two million base pairs at the site of a DNA double-strand break. γH2AX does not, itself, cause chromatin decondensation, but within 30 seconds of irradiation, RNF8 protein can be detected in association with γH2AX. RNF8 mediates extensive chromatin decondensation, through its subsequent interaction with CHD4, a component of the nucleosome remodeling and deacetylase complex NuRD.

DDB2 occurs in a heterodimeric complex with DDB1. This complex further complexes with the ubiquitin ligase protein CUL4A and with PARP1. This larger complex rapidly associates with UV-induced damage within chromatin, with half-maximum association completed in 40 seconds. The PARP1 protein, attached to both DDB1 and DDB2, then PARylates (creates a poly-ADP ribose chain) on DDB2 that attracts the DNA remodeling protein ALC1. Action of ALC1 relaxes the chromatin at the site of UV damage to DNA. This relaxation allows other proteins in the nucleotide excision repair pathway to enter the chromatin and repair UV-induced cyclobutane pyrimidine dimer damages.

After rapid chromatin remodeling, cell cycle checkpoints are activated to allow DNA repair to occur before the cell cycle progresses. First, two kinases, ATM and ATR are activated within 5 or 6 minutes after DNA is damaged. This is followed by phosphorylation of the cell cycle checkpoint protein Chk1, initiating its function, about 10 minutes after DNA is damaged.

DNA damage checkpoints
After DNA damage, cell cycle checkpoints are activated. Checkpoint activation pauses the cell cycle and gives the cell time to repair the damage before continuing to divide. DNA damage checkpoints occur at the G1/S and G2/M boundaries. An intra-S checkpoint also exists. Checkpoint activation is controlled by two master kinases, ATM and ATR. ATM responds to DNA double-strand breaks and disruptions in chromatin structure, whereas ATR primarily responds to stalled replication forks. These kinases phosphorylate downstream targets in a signal transduction cascade, eventually leading to cell cycle arrest. A class of checkpoint mediator proteins including BRCA1, MDC1, and 53BP1 has also been identified. These proteins seem to be required for transmitting the checkpoint activation signal to downstream proteins.

DNA damage checkpoint is a signal transduction pathway that blocks cell cycle progression in G1, G2 and metaphase and slows down the rate of S phase progression when DNA is damaged. It leads to a pause in cell cycle allowing the cell time to repair the damage before continuing to divide.

Checkpoint Proteins can be separated into four groups: phosphatidylinositol 3-kinase (PI3K)-like protein kinase, proliferating cell nuclear antigen (PCNA)-like group, two serine/threonine(S/T) kinases and their adaptors. Central to all DNA damage induced checkpoints responses is a pair of large protein kinases belonging to the first group of PI3K-like protein kinases-the ATM (Ataxia telangiectasia mutated) and ATR (Ataxia- and Rad-related) kinases, whose sequence and functions have been well conserved in evolution. All DNA damage response requires either ATM or ATR because they have the ability to bind to the chromosomes at the site of DNA damage, together with accessory proteins that are platforms on which DNA damage response components and DNA repair complexes can be assembled.

An important downstream target of ATM and ATR is p53, as it is required for inducing apoptosis following DNA damage. The cyclin-dependent kinase inhibitor p21 is induced by both p53-dependent and p53-independent mechanisms and can arrest the cell cycle at the G1/S and G2/M checkpoints by deactivating cyclin/cyclin-dependent kinase complexes.

The prokaryotic SOS response
The SOS response is the changes in gene expression in Escherichia coli and other bacteria in response to extensive DNA damage. The prokaryotic SOS system is regulated by two key proteins: LexA and RecA. The LexA homodimer is a transcriptional repressor that binds to operator sequences commonly referred to as SOS boxes. In Escherichia coli it is known that LexA regulates transcription of approximately 48 genes including the lexA and recA genes. The SOS response is known to be widespread in the Bacteria domain, but it is mostly absent in some bacterial phyla, like the Spirochetes. The most common cellular signals activating the SOS response are regions of single-stranded DNA (ssDNA), arising from stalled replication forks or double-strand breaks, which are processed by DNA helicase to separate the two DNA strands. In the initiation step, RecA protein binds to ssDNA in an ATP hydrolysis driven reaction creating RecA–ssDNA filaments. RecA–ssDNA filaments activate LexA autoprotease activity, which ultimately leads to cleavage of LexA dimer and subsequent LexA degradation. The loss of LexA repressor induces transcription of the SOS genes and allows for further signal induction, inhibition of cell division and an increase in levels of proteins responsible for damage processing.

In Escherichia coli, SOS boxes are 20-nucleotide long sequences near promoters with palindromic structure and a high degree of sequence conservation. In other classes and phyla, the sequence of SOS boxes varies considerably, with different length and composition, but it is always highly conserved and one of the strongest short signals in the genome. The high information content of SOS boxes permits differential binding of LexA to different promoters and allows for timing of the SOS response. The lesion repair genes are induced at the beginning of SOS response. The error-prone translesion polymerases, for example, UmuCD'2 (also called DNA polymerase V), are induced later on as a last resort. Once the DNA damage is repaired or bypassed using polymerases or through recombination, the amount of single-stranded DNA in cells is decreased, lowering the amounts of RecA filaments decreases cleavage activity of LexA homodimer, which then binds to the SOS boxes near promoters and restores normal gene expression.

Eukaryotic transcriptional responses to DNA damage
Eukaryotic cells exposed to DNA damaging agents also activate important defensive pathways by inducing multiple proteins involved in DNA repair, cell cycle checkpoint control, protein trafficking and degradation. Such genome wide transcriptional response is very complex and tightly regulated, thus allowing coordinated global response to damage. Exposure of yeast Saccharomyces cerevisiae to DNA damaging agents results in overlapping but distinct transcriptional profiles. Similarities to environmental shock response indicates that a general global stress response pathway exist at the level of transcriptional activation. In contrast, different human cell types respond to damage differently indicating an absence of a common global response. The probable explanation for this difference between yeast and human cells may be in the heterogeneity of mammalian cells. In an animal different types of cells are distributed among different organs that have evolved different sensitivities to DNA damage.

In general global response to DNA damage involves expression of multiple genes responsible for postreplication repair, homologous recombination, nucleotide excision repair, DNA damage checkpoint, global transcriptional activation, genes controlling mRNA decay, and many others. A large amount of damage to a cell leaves it with an important decision: undergo apoptosis and die, or survive at the cost of living with a modified genome. An increase in tolerance to damage can lead to an increased rate of survival that will allow a greater accumulation of mutations. Yeast Rev1 and human polymerase η are members of Y family translesion DNA polymerases present during global response to DNA damage and are responsible for enhanced mutagenesis during a global response to DNA damage in eukaryotes.

Pathological effects of poor DNA repair

Experimental animals with genetic deficiencies in DNA repair often show decreased life span and increased cancer incidence. For example, mice deficient in the dominant NHEJ pathway and in telomere maintenance mechanisms get lymphoma and infections more often, and, as a consequence, have shorter lifespans than wild-type mice. In similar manner, mice deficient in a key repair and transcription protein that unwinds DNA helices have premature onset of aging-related diseases and consequent shortening of lifespan. However, not every DNA repair deficiency creates exactly the predicted effects; mice deficient in the NER pathway exhibited shortened life span without correspondingly higher rates of mutation.

The maximum life spans of mice, naked mole-rats and humans are respectively ~3, ~30 and ~129 years. Of these, the shortest lived species, mouse, expresses DNA repair genes, including core genes in several DNA repair pathways, at a lower level than do humans and naked mole rats. Furthermore several DNA repair pathways in humans and naked mole-rats are up-regulated compared to mouse. These observations suggest that elevated DNA repair facilitates greater longevity.

If the rate of DNA damage exceeds the capacity of the cell to repair it, the accumulation of errors can overwhelm the cell and result in early senescence, apoptosis, or cancer. Inherited diseases associated with faulty DNA repair functioning result in premature aging, increased sensitivity to carcinogens and correspondingly increased cancer risk (see below). On the other hand, organisms with enhanced DNA repair systems, such as Deinococcus radiodurans, the most radiation-resistant known organism, exhibit remarkable resistance to the double-strand break-inducing effects of radioactivity, likely due to enhanced efficiency of DNA repair and especially NHEJ.

Longevity and caloric restriction
A number of individual genes have been identified as influencing variations in life span within a population of organisms. The effects of these genes is strongly dependent on the environment, in particular, on the organism's diet. Caloric restriction reproducibly results in extended lifespan in a variety of organisms, likely via nutrient sensing pathways and decreased metabolic rate. The molecular mechanisms by which such restriction results in lengthened lifespan are as yet unclear (see for some discussion); however, the behavior of many genes known to be involved in DNA repair is altered under conditions of caloric restriction. Several agents reported to have anti-aging properties have been shown to attenuate constitutive level of mTOR signaling, an evidence of reduction of metabolic activity, and concurrently to reduce constitutive level of DNA damage induced by endogenously generated reactive oxygen species.

For example, increasing the gene dosage of the gene SIR-2, which regulates DNA packaging in the nematode worm Caenorhabditis elegans, can significantly extend lifespan. The mammalian homolog of SIR-2 is known to induce downstream DNA repair factors involved in NHEJ, an activity that is especially promoted under conditions of caloric restriction. Caloric restriction has been closely linked to the rate of base excision repair in the nuclear DNA of rodents, although similar effects have not been observed in mitochondrial DNA.

The C. elegans gene AGE-1, an upstream effector of DNA repair pathways, confers dramatically extended life span under free-feeding conditions but leads to a decrease in reproductive fitness under conditions of caloric restriction. This observation supports the pleiotropy theory of the biological origins of aging, which suggests that genes conferring a large survival advantage early in life will be selected for even if they carry a corresponding disadvantage late in life.

Hereditary DNA repair disorders
Defects in the NER mechanism are responsible for several genetic disorders, including:
 * Xeroderma pigmentosum: hypersensitivity to sunlight/UV, resulting in increased skin cancer incidence and premature aging
 * Cockayne syndrome: hypersensitivity to UV and chemical agents
 * Trichothiodystrophy: sensitive skin, brittle hair and nails

Mental retardation often accompanies the latter two disorders, suggesting increased vulnerability of developmental neurons.

Other DNA repair disorders include:
 * Werner's syndrome: premature aging and retarded growth
 * Bloom's syndrome: sunlight hypersensitivity, high incidence of malignancies (especially leukemias).
 * Ataxia telangiectasia: sensitivity to ionizing radiation and some chemical agents

All of the above diseases are often called "segmental progerias" ("accelerated aging diseases") because those affected appear elderly and experience aging-related diseases at an abnormally young age, while not manifesting all the symptoms of old age.

Other diseases associated with reduced DNA repair function include Fanconi anemia, hereditary breast cancer and hereditary colon cancer.

Cancer
Because of inherent limitations in the DNA repair mechanisms, if humans lived long enough, they would all eventually develop cancer. There are at least 34 Inherited human DNA repair gene mutations that increase cancer risk. Many of these mutations cause DNA repair to be less effective than normal. In particular, Hereditary nonpolyposis colorectal cancer (HNPCC) is strongly associated with specific mutations in the DNA mismatch repair pathway. BRCA1 and BRCA2, two important genes whose mutations confer a hugely increased risk of breast cancer on carriers, are both associated with a large number of DNA repair pathways, especially NHEJ and homologous recombination.

Cancer therapy procedures such as chemotherapy and radiotherapy work by overwhelming the capacity of the cell to repair DNA damage, resulting in cell death. Cells that are most rapidly dividing – most typically cancer cells – are preferentially affected. The side-effect is that other non-cancerous but rapidly dividing cells such as progenitor cells in the gut, skin, and hematopoietic system are also affected. Modern cancer treatments attempt to localize the DNA damage to cells and tissues only associated with cancer, either by physical means (concentrating the therapeutic agent in the region of the tumor) or by biochemical means (exploiting a feature unique to cancer cells in the body). In the context of therapies targeting DNA damage response genes, the latter approach has been termed 'synthetic lethality'.

Perhaps the most well-known of these 'synthetic lethality' drugs is the poly(ADP-ribose) polymerase 1 (PARP1) inhibitor olaparib, which was approved by the Food and Drug Administration in 2015 for the treatment in women of BRCA-defective ovarian cancer. Tumor cells with partial loss of DNA damage response (specifically, homologous recombination repair) are dependent on another mechanism – single-strand break repair – which is a mechanism consisting, in part, of the PARP1 gene product. Olaparib is combined with chemotherapeutics to inhibit single-strand break repair induced by DNA damage caused by the co-administered chemotherapy. Tumor cells relying on this residual DNA repair mechanism are unable to repair the damage and hence are not able to survive and proliferate, whereas normal cells can repair the damage with the functioning homologous recombination mechanism.

Many other drugs for use against other residual DNA repair mechanisms commonly found in cancer are currently under investigation. However, synthetic lethality therapeutic approaches have been questioned due to emerging evidence of acquired resistance, achieved through rewiring of DNA damage response pathways and reversion of previously inhibited defects.

DNA repair defects in cancer
It has become apparent over the past several years that the DNA damage response acts as a barrier to the malignant transformation of preneoplastic cells. Previous studies have shown an elevated DNA damage response in cell-culture models with oncogene activation and preneoplastic colon adenomas. DNA damage response mechanisms trigger cell-cycle arrest, and attempt to repair DNA lesions or promote cell death/senescence if repair is not possible. Replication stress is observed in preneoplastic cells due to increased proliferation signals from oncogenic mutations. Replication stress is characterized by: increased replication initiation/origin firing; increased transcription and collisions of transcription-replication complexes; nucleotide deficiency; increase in reactive oxygen species (ROS).

Replication stress, along with the selection for inactivating mutations in DNA damage response genes in the evolution of the tumor, leads to downregulation and/or loss of some DNA damage response mechanisms, and hence loss of DNA repair and/or senescence/programmed cell death. In experimental mouse models, loss of DNA damage response-mediated cell senescence was observed after using a short hairpin RNA (shRNA) to inhibit the double-strand break response kinase ataxia telangiectasia (ATM), leading to increased tumor size and invasiveness. Humans born with inherited defects in DNA repair mechanisms (for example, Li-Fraumeni syndrome) have a higher cancer risk.

The prevalence of DNA damage response mutations differs across cancer types; for example, 30% of breast invasive carcinomas have mutations in genes involved in homologous recombination. In cancer, downregulation is observed across all DNA damage response mechanisms (base excision repair (BER), nucleotide excision repair (NER), DNA mismatch repair (MMR), homologous recombination repair (HR), non-homologous end joining (NHEJ) and translesion DNA synthesis (TLS). As well as mutations to DNA damage repair genes, mutations also arise in the genes responsible for arresting the cell cycle to allow sufficient time for DNA repair to occur, and some genes are involved in both DNA damage repair and cell cycle checkpoint control, for example ATM and checkpoint kinase 2 (CHEK2) – a tumor suppressor that is often absent or downregulated in non-small cell lung cancer.

Epigenetic DNA repair defects in cancer
Classically, cancer has been viewed as a set of diseases that are driven by progressive genetic abnormalities that include mutations in tumour-suppressor genes and oncogenes, and chromosomal aberrations. However, it has become apparent that cancer is also driven by epigenetic alterations.

Epigenetic alterations refer to functionally relevant modifications to the genome that do not involve a change in the nucleotide sequence. Examples of such modifications are changes in DNA methylation (hypermethylation and hypomethylation) and histone modification, changes in chromosomal architecture (caused by inappropriate expression of proteins such as HMGA2 or HMGA1) and changes caused by microRNAs. Each of these epigenetic alterations serves to regulate gene expression without altering the underlying DNA sequence. These changes usually remain through cell divisions, last for multiple cell generations, and can be considered to be epimutations (equivalent to mutations).

While large numbers of epigenetic alterations are found in cancers, the epigenetic alterations in DNA repair genes, causing reduced expression of DNA repair proteins, appear to be particularly important. Such alterations are thought to occur early in progression to cancer and to be a likely cause of the genetic instability characteristic of cancers.

Reduced expression of DNA repair genes causes deficient DNA repair. When DNA repair is deficient DNA damages remain in cells at a higher than usual level and these excess damages cause increased frequencies of mutation or epimutation. Mutation rates increase substantially in cells defective in DNA mismatch repair or in homologous recombinational repair (HRR). Chromosomal rearrangements and aneuploidy also increase in HRR defective cells.

Higher levels of DNA damage not only cause increased mutation, but also cause increased epimutation. During repair of DNA double strand breaks, or repair of other DNA damages, incompletely cleared sites of repair can cause epigenetic gene silencing.

Deficient expression of DNA repair proteins due to an inherited mutation can cause increased risk of cancer. Individuals with an inherited impairment in any of 34 DNA repair genes (see article DNA repair-deficiency disorder) have an increased risk of cancer, with some defects causing up to a 100% lifetime chance of cancer (e.g. p53 mutations). However, such germline mutations (which cause highly penetrant cancer syndromes) are the cause of only about 1 percent of cancers.

Frequencies of epimutations in DNA repair genes

Deficiencies in DNA repair enzymes are occasionally caused by a newly arising somatic mutation in a DNA repair gene, but are much more frequently caused by epigenetic alterations that reduce or silence expression of DNA repair genes. For example, when 113 colorectal cancers were examined in sequence, only four had a missense mutation in the DNA repair gene MGMT, while the majority had reduced MGMT expression due to methylation of the MGMT promoter region (an epigenetic alteration). Five different studies found that between 40% and 90% of colorectal cancers have reduced MGMT expression due to methylation of the MGMT promoter region.

Similarly, out of 119 cases of mismatch repair-deficient colorectal cancers that lacked DNA repair gene PMS2 expression, PMS2 was deficient in 6 due to mutations in the PMS2 gene, while in 103 cases PMS2 expression was deficient because its pairing partner MLH1 was repressed due to promoter methylation (PMS2 protein is unstable in the absence of MLH1). In the other 10 cases, loss of PMS2 expression was likely due to epigenetic overexpression of the microRNA, miR-155, which down-regulates MLH1.

In a further example, epigenetic defects were found in various cancers (e.g. breast, ovarian, colorectal and head and neck). Two or three deficiencies in the expression of ERCC1, XPF or PMS2 occur simultaneously in the majority of 49 colon cancers evaluated by Facista et al.

The chart in this section shows some frequent DNA damaging agents, examples of DNA lesions they cause, and the pathways that deal with these DNA damages. At least 169 enzymes are either directly employed in DNA repair or influence DNA repair processes. Of these, 83 are directly employed in repairing the 5 types of DNA damages illustrated in the chart.

Some of the more well studied genes central to these repair processes are shown in the chart. The gene designations shown in red, gray or cyan indicate genes frequently epigenetically altered in various types of cancers. Wikipedia articles on each of the genes highlighted by red, gray or cyan describe the epigenetic alteration(s) and the cancer(s) in which these epimutations are found. Review articles, and broad experimental survey articles also document most of these epigenetic DNA repair deficiencies in cancers.

Red-highlighted genes are frequently reduced or silenced by epigenetic mechanisms in various cancers. When these genes have low or absent expression, DNA damages can accumulate. Replication errors past these damages (see translesion synthesis) can lead to increased mutations and, ultimately, cancer. Epigenetic repression of DNA repair genes in accurate DNA repair pathways appear to be central to carcinogenesis.

The two gray-highlighted genes RAD51 and BRCA2, are required for homologous recombinational repair. They are sometimes epigenetically over-expressed and sometimes under-expressed in certain cancers. As indicated in the Wikipedia articles on RAD51 and BRCA2, such cancers ordinarily have epigenetic deficiencies in other DNA repair genes. These repair deficiencies would likely cause increased unrepaired DNA damages. The over-expression of RAD51 and BRCA2 seen in these cancers may reflect selective pressures for compensatory RAD51 or BRCA2 over-expression and increased homologous recombinational repair to at least partially deal with such excess DNA damages. In those cases where RAD51 or BRCA2 are under-expressed, this would itself lead to increased unrepaired DNA damages. Replication errors past these damages (see translesion synthesis) could cause increased mutations and cancer, so that under-expression of RAD51 or BRCA2 would be carcinogenic in itself.

Cyan-highlighted genes are in the microhomology-mediated end joining (MMEJ) pathway and are up-regulated in cancer. MMEJ is an additional error-prone inaccurate repair pathway for double-strand breaks. In MMEJ repair of a double-strand break, an homology of 5–25 complementary base pairs between both paired strands is sufficient to align the strands, but mismatched ends (flaps) are usually present. MMEJ removes the extra nucleotides (flaps) where strands are joined, and then ligates the strands to create an intact DNA double helix. MMEJ almost always involves at least a small deletion, so that it is a mutagenic pathway. FEN1, the flap endonuclease in MMEJ, is epigenetically increased by promoter hypomethylation and is over-expressed in the majority of cancers of the breast, prostate, stomach, neuroblastomas, pancreas, and lung. PARP1 is also over-expressed when its promoter region ETS site is epigenetically hypomethylated, and this contributes to progression to endometrial cancer and BRCA-mutated serous ovarian cancer. Other genes in the MMEJ pathway are also over-expressed in a number of cancers (see MMEJ for summary), and are also shown in cyan.

Genome-wide distribution of DNA repair in human somatic cells
Differential activity of DNA repair pathways across various regions of the human genome causes mutations to be very unevenly distributed within tumor genomes. In particular, the gene-rich, early-replicating regions of the human genome exhibit lower mutation frequencies than the gene-poor, late-replicating heterochromatin. One mechanism underlying this involves the histone modification H3K36me3, which can recruit mismatch repair proteins, thereby lowering mutation rates in H3K36me3-marked regions. Another important mechanism concerns nucleotide excision repair, which can be recruited by the transcription machinery, lowering somatic mutation rates in active genes and other open chromatin regions.

Epigenetic alterations due to DNA repair
Damage to DNA is very common and is constantly being repaired. Epigenetic alterations can accompany DNA repair of oxidative damage or double-strand breaks. In human cells, oxidative DNA damage occurs about 10,000 times a day and DNA double-strand breaks occur about 10 to 50 times a cell cycle in somatic replicating cells (see DNA damage (naturally occurring)). The selective advantage of DNA repair is to allow the cell to survive in the face of DNA damage. The selective advantage of epigenetic alterations that occur with DNA repair is not clear.

Repair of oxidative DNA damage can alter epigenetic markers
In the steady state (with endogenous damages occurring and being repaired), there are about 2,400 oxidatively damaged guanines that form 8-oxo-2'-deoxyguanosine (8-OHdG) in the average mammalian cell DNA. 8-OHdG constitutes about 5% of the oxidative damages commonly present in DNA. The oxidized guanines do not occur randomly among all guanines in DNA. There is a sequence preference for the guanine at a methylated CpG site (a cytosine followed by guanine along its 5' → 3' direction and where the cytosine is methylated (5-mCpG)). A 5-mCpG site has the lowest ionization potential for guanine oxidation.

Oxidized guanine has mispairing potential and is mutagenic. Oxoguanine glycosylase (OGG1) is the primary enzyme responsible for the excision of the oxidized guanine during DNA repair. OGG1 finds and binds to an 8-OHdG within a few seconds. However, OGG1 does not immediately excise 8-OHdG. In HeLa cells half maximum removal of 8-OHdG occurs in 30 minutes, and in irradiated mice, the 8-OHdGs induced in the mouse liver are removed with a half-life of 11 minutes.

When OGG1 is present at an oxidized guanine within a methylated CpG site it recruits TET1 to the 8-OHdG lesion (see Figure). This allows TET1 to demethylate an adjacent methylated cytosine. Demethylation of cytosine is an epigenetic alteration.

As an example, when human mammary epithelial cells were treated with H2O2 for six hours, 8-OHdG increased about 3.5-fold in DNA and this caused about 80% demethylation of the 5-methylcytosines in the genome. Demethylation of CpGs in a gene promoter by TET enzyme activity increases transcription of the gene into messenger RNA. In cells treated with H2O2, one particular gene was examined, BACE1. The methylation level of the BACE1 CpG island was reduced (an epigenetic alteration) and this allowed about 6.5 fold increase of expression of BACE1 messenger RNA.

While six-hour incubation with H2O2 causes considerable demethylation of 5-mCpG sites, shorter times of H2O2 incubation appear to promote other epigenetic alterations. Treatment of cells with H2O2 for 30 minutes causes the mismatch repair protein heterodimer MSH2-MSH6 to recruit DNA methyltransferase 1 (DNMT1) to sites of some kinds of oxidative DNA damage. This could cause increased methylation of cytosines (epigenetic alterations) at these locations.

Jiang et al. treated HEK 293 cells with agents causing oxidative DNA damage, (potassium bromate (KBrO3) or potassium chromate (K2CrO4)). Base excision repair (BER) of oxidative damage occurred with the DNA repair enzyme polymerase beta localizing to oxidized guanines. Polymerase beta is the main human polymerase in short-patch BER of oxidative DNA damage. Jiang et al. also found that polymerase beta recruited the DNA methyltransferase protein DNMT3b to BER repair sites. They then evaluated the methylation pattern at the single nucleotide level in a small region of DNA including the promoter region and the early transcription region of the BRCA1 gene. Oxidative DNA damage from bromate modulated the DNA methylation pattern (caused epigenetic alterations) at CpG sites within the region of DNA studied. In untreated cells, CpGs located at −189, −134, −29, −19, +16, and +19 of the BRCA1 gene had methylated cytosines (where numbering is from the messenger RNA transcription start site, and negative numbers indicate nucleotides in the upstream promoter region). Bromate treatment-induced oxidation resulted in the loss of cytosine methylation at −189, −134, +16 and +19 while also leading to the formation of new methylation at the CpGs located at −80, −55, −21 and +8 after DNA repair was allowed.

Homologous recombinational repair alters epigenetic markers
At least four articles report the recruitment of DNA methyltransferase 1 (DNMT1) to sites of DNA double-strand breaks. During homologous recombinational repair (HR) of the double-strand break, the involvement of DNMT1 causes the two repaired strands of DNA to have different levels of methylated cytosines. One strand becomes frequently methylated at about 21 CpG sites downstream of the repaired double-strand break. The other DNA strand loses methylation at about six CpG sites that were previously methylated downstream of the double-strand break, as well as losing methylation at about five CpG sites that were previously methylated upstream of the double-strand break. When the chromosome is replicated, this gives rise to one daughter chromosome that is heavily methylated downstream of the previous break site and one that is unmethylated in the region both upstream and downstream of the previous break site. With respect to the gene that was broken by the double-strand break, half of the progeny cells express that gene at a high level and in the other half of the progeny cells expression of that gene is repressed. When clones of these cells were maintained for three years, the new methylation patterns were maintained over that time period.

In mice with a CRISPR-mediated homology-directed recombination insertion in their genome there were a large number of increased methylations of CpG sites within the double-strand break-associated insertion.

Non-homologous end joining can cause some epigenetic marker alterations
Non-homologous end joining (NHEJ) repair of a double-strand break can cause a small number of demethylations of pre-existing cytosine DNA methylations downstream of the repaired double-strand break. Further work by Allen et al. showed that NHEJ of a DNA double-strand break in a cell could give rise to some progeny cells having repressed expression of the gene harboring the initial double-strand break and some progeny having high expression of that gene due to epigenetic alterations associated with NHEJ repair. The frequency of epigenetic alterations causing repression of a gene after an NHEJ repair of a DNA double-strand break in that gene may be about 0.9%.

Evolution
The basic processes of DNA repair are highly conserved among both prokaryotes and eukaryotes and even among bacteriophages (viruses which infect bacteria); however, more complex organisms with more complex genomes have correspondingly more complex repair mechanisms. The ability of a large number of protein structural motifs to catalyze relevant chemical reactions has played a significant role in the elaboration of repair mechanisms during evolution. For an extremely detailed review of hypotheses relating to the evolution of DNA repair, see.

The fossil record indicates that single-cell life began to proliferate on the planet at some point during the Precambrian period, although exactly when recognizably modern life first emerged is unclear. Nucleic acids became the sole and universal means of encoding genetic information, requiring DNA repair mechanisms that in their basic form have been inherited by all extant life forms from their common ancestor. The emergence of Earth's oxygen-rich atmosphere (known as the "oxygen catastrophe") due to photosynthetic organisms, as well as the presence of potentially damaging free radicals in the cell due to oxidative phosphorylation, necessitated the evolution of DNA repair mechanisms that act specifically to counter the types of damage induced by oxidative stress. The mechanism by which this came about, however, is unclear.

Rate of evolutionary change
On some occasions, DNA damage is not repaired or is repaired by an error-prone mechanism that results in a change from the original sequence. When this occurs, mutations may propagate into the genomes of the cell's progeny. Should such an event occur in a germ line cell that will eventually produce a gamete, the mutation has the potential to be passed on to the organism's offspring. The rate of evolution in a particular species (or, in a particular gene) is a function of the rate of mutation. As a consequence, the rate and accuracy of DNA repair mechanisms have an influence over the process of evolutionary change. DNA damage protection and repair does not influence the rate of adaptation by gene regulation and by recombination and selection of alleles. On the other hand, DNA damage repair and protection does influence the rate of accumulation of irreparable, advantageous, code expanding, inheritable mutations, and slows down the evolutionary mechanism for expansion of the genome of organisms with new functionalities. The tension between evolvability and mutation repair and protection needs further investigation.

Technology
A technology named clustered regularly interspaced short palindromic repeat (shortened to CRISPR-Cas9) was discovered in 2012. The new technology allows anyone with molecular biology training to alter the genes of any species with precision, by inducing DNA damage at a specific point and then altering DNA repair mechanisms to insert new genes. It is cheaper, more efficient, and more precise than other technologies. With the help of CRISPR–Cas9, parts of a genome can be edited by scientists by removing, adding, or altering parts in a DNA sequence.

title: DNA repair


text:
Isaac van Ostade

Isaac van Ostade (bapt. June 2, 1621 – buried October 16, 1649) was a Dutch genre and landscape painter.

Biography
Van Ostade was born in Haarlem. He began his studies under his brother, Adriaen, with whom he remained until 1641, when he started his own practice. At an early period he felt the influence of Rembrandt, and this is apparent in a Slaughtered Pig of 1639, in the gallery of Augsburg. He soon found a style more suited to his own inclinations. He produced pictures in 1641–1642 on the lines of his brother – amongst these, the Five Senses, which Adrian afterwards represented by a Man reading a Paper, a Peasant tasting Beer, a Rustic smearing his Sores with Ointment and a Countryman sniffing at a Snuff-box. A specimen of Isaac's work at this period may be seen in the Laughing Boor with a Pot of Beer, in the museum of Amsterdam; the cottage interior, with two peasants and three children near a fire, in the Berlin museum; a Concert, with people listening to singers accompanied by a piper and flute player, and a Boor stealing a Kiss from a Woman, in the Lacaze collection at the Louvre.

The interior at Berlin is lighted from a casement in the same Rembrandtesque style as Adrian's interior of 1643 at the Louvre. He received low prices for this kind of painting, in which he could only remain subordinate to his brother. Gradually he abandoned Adriaen's cottage subjects for landscapes in the fashion of Esaias van de Velde and Salomon van Ruysdael. Once only, in 1645, he reverted to the earlier mode, when he produced the Slaughtered Pig, with a boy puffing out a bladder, in the museum of Lille.

Isaac's progress in his new path was greatly facilitated by his previous experience as a figure painter; and, although he now selected his subjects either from village high streets or frozen canals, he gave fresh life to the scenes by depicting animated groups of people with a refined and searching study of picturesque contrasts. He did not live long enough to bring his art to the highest perfection. He died on 16 October 1649 in Haarlem, having painted about 400 pictures (see H. de Groot, 1910).

The first manifestation of Isaac's surrender of Adriaen's style is apparent in 1644 when the skating and sledging scenes were executed which we see in the Lacaze collection and the galleries of the Hermitage, Antwerp and Lille. Three of these examples bear the artists name, spelled Isack van Ostade, and the dates of 1644 and 1645. The roadside inns, with halts of travellers, form a compact series from 1646 to 1649. This is the last form of Isaac's art and has very distinct peculiarities. The air which pervades his composition is warm and sunny, yet mellow and hazy, as if the sky were veiled with a vapour coloured by moor smoke. The trees are rubbings of umber, in which the prominent foliage is tipped with touches hardened in a liquid state by amber varnish mediums. The same principle applied to details such as glazed bricks or rents in the mud lining of cottages gives an unreal and conventional stamp to them.

These quirks are overcome by his broad contrasts of light and shade and the masterly figures of horses, riders, travellers, rustics, quarrelling children, dogs, poultry and cattle. A favorite place is always given to the white horse, which seems as invariable an accompaniment as the grey in the skirmishes and fairs of Philip Wouwerman.

Isaac displays the best qualities in winter scenes. The absence of foliage, the crisp atmosphere and the calm air of cold January days, unsullied by smoke or vapour, preclude the use of the brown tinge, and leave the painter no choice but to ring the changes with a great variety of opal tints. Then the figures emerge with masterly effect on the light background. Amongst the roadside inns it is worth noting those in the collections of Buckingham Palace, the National Gallery, London, the Wallace Collection and Holford collections in England, the Louvre, Berlin, Hermitage and Rotterdam museums and the Rothschild collection at Vienna. The finest of the ice scenes is the famous one at the Louvre.

For paintings and etchings see Les Fréres Ostade, by Marguerite van de Wiele (Paris, 1893). For his etchings see L'Œuvre d'Ostade, cu description des eaux-fortes de ce maître, etc., by Auguste d'Orange (1860); and Catalogue raisonné de toutes les estampes qui forment l'œuvre grave d'Adrian van Ostade, by L.E. Faucheux (Paris, 1862).

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Isaac van Ostade


text:
Christopher Daykin

Christopher David Daykin CB (born 18 July 1948) is a British actuary and civil servant. He was the head of the United Kingdom Government Actuary’s Department (GAD) from 1989 to 2007 where he worked on social security, pension fund consultancy, national pension policy, population projections, risk management and pension reform. He is the second-longest holder of the post.

After graduating from Cambridge University with an honours degree in mathematics in 1970, Daykin qualified as a Fellow of the Institute of Actuaries in 1973 where he served as President between 1994 and 1996. He was also a President of the International Forum of Actuarial Associations in 1996-97 and was awarded the Medallist award from the International Actuarial Association in 2014.

In 1993 New Year Honours, he was appointed a Companion of the Order of the Bath (CB).

In 1995, he was presented with an Honorary Doctor of Science from City University of London.

Daykin was awarded the Gold Medal of the Institute of Actuaries in 1998 and the Medal of Merit of the International Social Security Association in 2007.

Daykin has published reports on issues such as the state pension scheme and co-authored the book Practical Risk Theory for Actuaries.

Early life
He has a first class mathematics degree from Pembroke College, Cambridge University and attended Merchant Taylors' School, London.

title: Christopher Daykin


text:
Talk:Trapain Law

this place appears as Traprain Law in all the books and maps I've looked at, including an Ordnance Survey atlas and a Johnston road atlas of about 1940 (street plans omitted because of the war). Suggest this page be redirected.

p.s. check out Arthur's Seat dave souza 12:20, 24 Jul 2004 (UTC)

found out how to redirect, done. dave souza 22:26, 24 Jul 2004 (UTC)

title: Talk:Trapain Law


text:
User talk:PrometheusOne

Welcome to Wikipedia, but please do not cut and pase copyrighted material into the 'pedia. Cheers, Dunc_Harris|☺ 12:25, 24 Jul 2004 (UTC)

 * Prometheus1, it looks OK. I'm sure Duncan meant well (we do get a lot of cut and pastes) and he may have inadvertantly found something that contained keywords in your text and saw that you were a new user (most copyvio's come from new users) and jumped a bit fast. I have restored your text. --Lexor|Talk

Yeah, sorry. I googled one of the phrases and it came up; it seems by chance. Nice article, btw. Dunc_Harris|☺ 16:23, 24 Jul 2004 (UTC)

 * By the way, are you by any chance connected to the User:Prometheus? If you have lost your password, I think it can be reset.  That way you keep all your contribs together.  Cheers. --Lexor|Talk 12:55, 24 Jul 2004 (UTC)

 * no im not the other prometheus

I fixed the problem on DNA repair, the problem is that you started the line with a space. Whenever you start the line with a space, it will format the rest of the line (and paragraph) as   formatted text, this is to allow for verbatim ASCII art the be included inline, like this:

++ | a box with text   | ++

You need to read How to edit a page, see towards the bottom of the table it describes what happens when a line starts with a space. Cheers, --Lexor|Talk 14:09, 25 Jul 2004 (UTC)

Also, could you please put add information regarding the copyright status of the images you contributed to their image pages: Image:Dnarepair1.jpg and Image:Dnadamage.jpg. I see that they have (C) Copyright Prometheus 2004 (which I assume is you), even if so, you need to indicate what license you are contributing the images under, otherwise it defaults to copyright to you (we recommend the GFDL, but you can dual-license under other licenses such as the Creative Commons) See Image copyright tags, Copyrights and Copyright FAQ for more. --Lexor|Talk 14:09, 25 Jul 2004 (UTC)

Hi Prometheus,

Just a comment. You might not realise how harsh your replies to User:Shibboleth sound. Remember, just about everyone here is a volunteer working towards the same goal - to make a really good free encyclopedia. I understand that it doesn't always feel that way when someone criticises an article that you have put a lot of effort into.

There are a number of issues here, but first up let me say that as a scientist, I think the article on DNA repair is an excellent addition to Wikipedia, particularly the graphics (see below). However proposing an article on Featured article candidates is specifically intended to illicit critism, usually objections, with a view to improving an article. If you check the archive of previous candidates, you will see that by far the most common objection is that "the writing could be improved". Sometimes I think there is too much emphasis on writing style, but it often correct. I'm sure this is all that User:Shibboleth was saying.

The intention behind featured articles often seems to get confused (and I'm not totaly certain what they are myself). I suspect many people want FA status to try and get an article on the front page, but that is only one of the side effects. I'm sure you've read the guidelines at What is a featured article. I think the intention is best summarised as "hey look at this featured article, if more of Wikipedia's articles were like this it would be really good". But that isn't to say that every article should be like that. In particular it may or may not be a good idea to simplify the writing in DNA repair. It could be a better idea to keep it somewhat technical to preserve accuracy and detail, but then we wouldn't be able to point to it as a featured article and say "hey everyone write like this" because most people won't be able to. -- Solipsist 08:36, 7 Aug 2004 (UTC)

 * Hello again Prometheus - It looks like User:Shibboleth is happy to roll back the discussion on Featured article candidates. Its really a job for a sysop, so do you have any objection if I ask User:Raul654 to move the discussion over to your talk pages here, and replace Shibboleth's 'object' with one from myself as outlined above? -- Solipsist 20:33, 7 Aug 2004 (UTC)

Hi again,

Just another note about the images on DNA repair (which look really good). Someone else on Featured article candidates has commented about clarifying the copyright attribution on these images. Its perfectly OK to upload images with copyright restrictions as long as the licensing is clarified on the Image description page, preferably with one of the templates in image copyright tags. Personally I tend to prefer some of the Creative Commons licenses.

However, I have seen some discussion elsewhere on Wikipedia, that the copyright and licensing of the majority of images is considered a significant problem for the GFDL status of Wikipedia itself, particularly with respect to possible print version. I've even seen one person say that it is possible that all images which are neither GFDL nor public domain could be deleted some time in the future. -- Solipsist 08:52, 7 Aug 2004 (UTC)

Wikibooks
Hi Prometheus1. I feel that with only a little more editing that the current version of DNA repair should be a FA (and is within the scope of wikipedia), but what I was thinking was that if you wanted to expand the article even further and make it even more detailed, you could do it on the sister project. This might also be a possible resolution to the discussions on FAC, since a detailed article on DNA repair (i.e. non-"dumbed-down") would be 100% and entirely within the scope of wikibooks. This way, we could keep a somewhat less technical encyclopedia version at DNA repair and cross-wikilink with the as-technical-as-you-want-it version at DNA repair. Just a thought. That way people interested in more details can easily access it. Cheers, --Lexor|Talk 11:31, 9 Aug 2004 (UTC)

DNA repair copyright issues
Prometheus - I've been asked to look into the DNA repair FAC nomination. I'm the guy who (sorta) runs the Featured article candidates page. The objections fall into two categories - copyright issues and the use of technical jargon. Since there's a lot of touchy feelings centered around the latter, I'm going to totally ignore it (at least for the time being) and instead work with you to resolve the copyright issues. There are three pictures on that page (very nice ones, too). On the image page for each of them (such as Image:Dnadamage.jpg) there should be information on the source and copyright status/license. (for an example, see Image:Coral sea.jpg). Could you fill this information in? It shouldn't take you more than a few minutes, and it would help the FAC nomination greatly if you did. Also, if you made those images yourself, the copyright tag in the picture itself should be removed and placed on the image page instead. →Raul654 20:11, Aug 9, 2004 (UTC)
 * With respect, if I have the term "jargon" - which means pretentious and meaningless language - applied to this article once more, I will simply withdraw it and be done with it. Cheers. prometheus1 23:48, 9 Aug 2004 (UTC)
 * Prometheus, thanks for updating the image copyright information. You say reproduced permission from the author (presumably you), but that doesn't indicate what redistribution status the image has.  If you want to license the image under the same license as your text (i.e. the GFDL), then you can simply include the tag  in the description page, otherwise it is not clear whether third-parties can redistribute the image.  You can also choose from a number of other licenses (see Image copyright tags), but the GFDL is the simplest.  --Lexor|Talk 10:12, 10 Aug 2004 (UTC)
 * Thank you for tagging the images. Another point, however - you say to credit the author of the images, but you don't say who that is. →Raul654 19:10, Aug 10, 2004 (UTC)
 * Hi Raul654, Prometheus1. Technical copyright matter here. Prometheus, would it terribly hurt you to licence those images under GFDL? Note that you retain your copyright when doing so. The wikipedia generally would benefit from images which are either GFDL or GFDL compatible whenever we can. "free for non-commercial use" is not GFDL compatible, and should be avoided for new content if possible IMHO. Otherwise I think the article is most excellent indeed! (disclaimer: I'm a biologist :-P ) Kim Bruning 11:57, 11 Aug 2004 (UTC)

Thymine dimerism
Hello, clearly you are an expert on biochemistry (I am not!) and DNA (your page on DNA repair is nice!), I've added a bit on thymine dimerization as the cause of sterilization by UV light to the sterilization section of that page. Is it correct by you?--Deglr6328 07:30, 13 Aug 2004 (UTC)

Redirects
Hello. Check out Redirect and learn a simple trick to take anyone who clicks on one title directly to another; no need to make a page saying to "see: (some other title)". Cheers, -- Infrogmation 03:53, 22 Aug 2004 (UTC)

DNA Repair image
Hi Prometheus,

Congrats on reaching FAC.

Like the new lead image, but I just wanted to make a slightly different comment on the other images. Various people have expressed concern about their copyright status WRT Wikipedia, but if Raul is happy with it now, it must be OK. However, you might want to check whether you can mark copyright under a pseudonym such as Prometheus. I'm not a lawyer, but it might be safer to mark them copyright 'Harold Brenner' (assuming that is correct). -- Solipsist 11:37, 28 Aug 2004 (UTC)
 * You have a point prometheus1 05:48, 29 Aug 2004 (UTC)

Hi, Prometheus1. Thanks for changing that confusing sentence. Could you look at the picture entitled 'Poor DNA repair induces pathology'? Can you change 'senesence' to 'senescence' please. Axl 11:22, 19 Nov 2004 (UTC)
 * Easier said than done. But it is time for an update on that image. Thanks for pointing it out! prometheus1

Evolution of diagnosis
Hi Prometheus, well done on this article. However, the title is rather unlinkable, and I would argue that "evolution" is not quite the word. These developments have been saltatory (e.g. with several revolutions). I'm merging it with diagnosis, which will probably strengthen both articles. Please discuss if you object. JFW | T@lk  15:43, 8 Sep 2004 (UTC)

 * Diagnosis needs more work now.
 * Nothing to be affraid of. Perhaps we should merge in differential diagnosis as well. JFW | T@lk  11:20, 10 Sep 2004 (UTC)

Lesch-Nyhan syndrome
hey there i'm currently using you damaged chromosome image for this article Lesch-Nyhan syndrome and i'm wondering if you could come up with anything better? --Larsie 23:24, 9 Nov 2004 (UTC)

Unverified images
Hi! Thanks for uploading the following images:

 * Image:Dnarepair.jpg
 * Image:Dna_damage.jpg
 * Image:Dna_repair.jpg

I notice it currently doesn't have an image copyright tag. Could you add one to let us know its copyright status? (You can use if you release it under the GNU Free Documentation License,  if you claim fair use, etc.) If you don't know what any of this means, just let me know at my talk page where you got the images and I'll tag them for you. Thanks so much. [[User:Poccil|Peter O. (Talk, automation script)]] 04:04, Dec 11, 2004 (UTC)

P.S. You can help tag other images at User:Yann/Untagged_Images. Thanks again.

DNA repair FARC
I see you haven't been around in a while, but on the off chance that you are still checking this page, you might want to know that DNA repair is currently a Featured article removal candidate. The objection centered around the lack of references, which I have mostly fixed in the text, as well as doing some rewriting/copyediting. However, there are no references for the two images you created, Image:dnadamage.jpg and Image:dnarepair1.jpg, and I haven't been able to track down sources that confirm every element in the pathways. Yes, this was from 2004, but if you see this and have those references handy, it would be very useful. Opabinia regalis 20:02, 26 May 2006 (UTC)

Proposed deletion of NeoSENS
A proposed deletion template has been added to the article NeoSENS, suggesting that it be deleted according to the proposed deletion process. All contributions are appreciated, but this article may not satisfy Wikipedia's criteria for inclusion, and the deletion notice should explain why (see also "What Wikipedia is not" and Wikipedia's deletion policy). You may prevent the proposed deletion by removing the  notice, but please explain why you disagree with the proposed deletion in your edit summary or on its talk page.

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Survey request
Hi, Prometheus1 I need your help. I am working on a research project at Boston College, studying creation of medical information on Wikipedia. You are being contacted because you have been identified as an important contributor to one or more articles.

Would you will be willing to answer a few questions about your experience? We've done considerable background research, but we would also like to gather the insight of the actual editors. Details about the project can be found at the user page of the project leader, geraldckane. Survey questions can be found at geraldckane/medsurvey. Your privacy and confidentiality will be strictly protected!

The questions should only take a few minutes. I hope you will be willing to complete the survey, as we do value your insight. Please do not hesitate to contact me or Professor Kane if you have any questions. Thank You, BCproject (talk) 05:18, 3 August 2008 (UTC) -- Certainly. Please provide an email address. prometheus1 (talk) 11:58, 13 December 2008 (UTC)

Image:Dnadamage.jpg listed for deletion
An image or media file that you uploaded or altered, Image:Dnadamage.jpg, has been listed at Images and media for deletion. Please see the to see why this is (you may have to search for the title of the image to find its entry), if you are interested in it not being deleted. Jordan 1972 (talk) 21:43, 21 October 2008 (UTC)

Image:Dnarepair1.jpg listed for deletion
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Disambiguation link notification for September 12
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Orphaned non-free media (File:Weightloss Complete package.gif)
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Your account will be renamed
Hello,

The developer team at Wikimedia is making some changes to how accounts work, as part of our on-going efforts to provide new and better tools for our users like cross-wiki notifications. These changes will mean you have the same account name everywhere. This will let us give you new features that will help you edit and discuss better, and allow more flexible user permissions for tools. One of the side-effects of this is that user accounts will now have to be unique across all 900 Wikimedia wikis. See the announcement for more information.

Unfortunately, your account clashes with another account also called Prometheus1. To make sure that both of you can use all Wikimedia projects in future, we have reserved the name Prometheus1~enwiki that only you will have. If you like it, you don't have to do anything. If you do not like it, you can pick out a different name. If you think you might own all of the accounts with this name and this message is in error, please visit Special:MergeAccount to check and attach all of your accounts to prevent them from being renamed.

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ArbCom elections are now open!
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DNA repair Featured article review
I have nominated DNA repair for a featured article review here. Please join the discussion on whether this article meets featured article criteria. Articles are typically reviewed for two weeks. If substantial concerns are not addressed during the review period, the article will be moved to the Featured Article Removal Candidates list for a further period, where editors may declare "Keep" or "Delist" the article's featured status. The instructions for the review process are here. Sandy Georgia (Talk)  22:52, 14 June 2020 (UTC)

title: User talk:PrometheusOne


text:
Tin Ujević

Augustin Josip "Tin" Ujević (5 July 1891 – 12 November 1955) was a Croatian poet, considered by many to be the greatest poet in 20th century Croatian literature.

From 1921, he ceased to sign his name as Augustin, thereafter using the signature Tin Ujević.

Biography
Ujević was born in Vrgorac, a small town in the Dalmatian hinterland, and attended school in Imotski, Makarska, Split and Zagreb. He completed Classical Gymnasium in Split, and in Zagreb he studied Croatian language and literature, classical Philology, Philosophy, and Aesthetics.

In 1909, while studying literature, his first sonnet "Za novim vidicima" (Towards New Horizons) appeared in the journal Mlada Hrvatska (Young Croatia). After the assassination attempts on the ban Slavko Cuvaj in 1912, Ujević became active in the Nationalist youth movement and was repeatedly imprisoned. On the eve of the First World War, he lived briefly in Dubrovnik, Šibenik, Zadar, Rijeka and for a longer time in Split. The crucial period for his political and poetic consciousness was his visit to Paris (1913–19).

After the death of A.G. Matoš in 1914, Ujević published an essay about his teacher in the literary magazine Savremenik. That same year the anthology of poetry inspired by Matoš, "Hrvatska mlada lirika" (Croatian Young Lyrics) brought together the work of 12 young poets, including 10 poems by Tin Ujević. Also in that year, Ujević joined the French Foreign Legion, though he left again after 3 months at the urging of Frano Supilo.

In 1919, Ujević returned to Zagreb. Around that time he wrote two autobiographical essays "Mrsko Ja" (Hateful Me, 1922) examining his political beliefs, which he described as disenchanted, and "Ispit savjesti" (Examination of Conscience, published in 1923 in the journal Savremenik), which he himself called a "sleepwalking sketch". It is considered to be one of the most moving confessional texts in Croatian literature, in which an author mercilessly examines their own past.

Ujević lived from 1920 to 1926 in Belgrade, then he moved between Split and Zagreb, back to Belgrade, then to Split again. In 1920 his first anthology of poetry "Lelek sebra" (Cry of a slave) was published in Belgrade, and in 1922 his poem "Visoki jablani" (High Poplars) appeared in the journal Putevi (Roads).

He was well known in bohemian circles in Belgrade and a frequent guest at Hotel Moskva and Skadarlija.

During the years 1930–37, Ujević lived in Sarajevo, then 1937–1940 in Split, finally moving back to Zagreb, where he lived until his death in 1955.

From 1941 to 1945 he did not publish a single book, earning his living as a journalist and translator. Ujević held a post in the Independent State of Croatia as a translator, and continued to publish some material. For this reason, he was forbidden by the Yugoslav government from continuing with his literary career for several years. In the last days of 1950 a selection of his work was published in Zagreb, under the title "Rukovet" ("Handful"). Ujević died on 12 November 1955 and is buried at Mirogoj Cemetery in Zagreb.

Legacy
In addition to his poetry, Tin Ujević also wrote essays, short stories, serials (feuilletons), studies on foreign and domestic authors, and he translated philosophical discussions from many foreign languages.

He translated numerous works of poetry, novels and short stories into Croatian (Edgar Allan Poe, Walt Whitman, Marcel Proust, Joseph Conrad, Benvenuto Cellini, George Meredith, Emile Verhaeren, Arthur Rimbaud, André Gide, among others ).

He wrote more than ten books of essays, poetry in prose and meditations — but his enduring strength lies chiefly in his poetic works. At first a follower of Silvije Strahimir Kranjčević and more especially A.G. Matoš, Ujević soon moved on and developed his own independent voice.

He preferred the French and American modernists such as Charles Baudelaire, Arthur Rimbaud and Walt Whitman, whose work he translated. His first collections Lelek sebra, and Kolajna, inspired by his years in Paris, are considered the peak of modern Croatian lyrical poetry.

From those original first books grew a body of work that is a classic of Croatian literature, and according to the British poet Clive Wilmer, "Tin Ujević was one of the last masters of European Symbolism". Poet and writer Anne Stevenson says his "melancholy, turn-of-the-century lyricism" is comparable to that of Thomas Hardy, of Edward Thomas, and of early Yeats".

British poet Richard Berengarten, who has translated some of Ujević's best works into English, writes "'Although Tin's major achievement is as a lyricist, his oeuvre is much broader than lyric alone. He was a writer of profound and discerning intellect, broad and capacious interests, inquisitive appetite and eclectic range.'"There are some 380 records about Tin Ujević's works in the catalogue of the National and University Library in Zagreb, and part of his literary heritage is preserved in the Library's Manuscripts and Old Books Collection. Ujević published his writings in all renowned newspapers and journals, in which numerous articles about Ujević were published, and part of that material in digital format is available at the Portal of Digitized Croatian Newspapers and Journals.

The Tin Ujević Award is the most prestigious poetry award in Croatia. In 2003, the Jadrolinija ferry, MV Tin Ujević was named for the poet. In 2005, Hrvatska Pošta issued a stamp in their series of Famous Croats: Tin Ujević on the 50th anniversary of his death. By 2008, a total of 122 streets in Croatia were named after Ujević, making him the ninth most common person for whom streets were named in Croatia. Six streets in Serbia are named after Ujević.

Works
His collected works, Sabrana djela (1963–1967) were published in 17 volumes. Individually and within selected works, Izabrana djela, numerous editions of his poems, essays and studies were published.
 * Lelek sebra (Cry of a slave), 1920, Belgrade (in Cyrillic, ekavian)
 * Kolajna (Necklace), 1926, Belgrade (in Cyrillic, ekavian)
 * Auto na korzu (Car on the promenade) 1932
 * Ojađeno zvono (Heavy-hearted bell) 1933, Zagreb
 * Skalpel kaosa (Scalpel of chaos) 1938, Zagreb
 * Ljudi za vratima gostionice (People behind inn doors) 1938, Zagreb
 * Žedan kamen na studencu (Thirsty stone at the wellspring), 1954, Zagreb

title: Tin Ujević


text:
Electromagnetic cavity

An electromagnetic cavity is a cavity that acts as a container for electromagnetic fields such as photons, in effect containing their wave function inside. The size of the cavity determines the maximum photon wavelength that can be trapped. Additionally, it produces quantized energy levels for trapped charged particles like electrons and protons. The Earth's magnetic field in effect places the Earth in an electromagnetic cavity.

Physical description of electromagnetic cavities
Electromagnetic cavities are represented by potential wells, also called boxes, which can be of limited or unlimited depth V0.

Quantum-mechanic boxes are described by the time-independent Schrödinger equation:

 * $$\left[ - \frac{\hbar^2}{2m} \nabla^2 + V(\mathbf{r}) \right] \psi(\mathbf{r}) = E \psi (\mathbf{r}),$$

with the additional boundary conditions which leads to real solutions for the wave functions if the net energy of the particle is negative., i.e. if the particle is in a bound state.
 * the wave function is confined to the box (infinite deep potential well) or approaches zero as the distance from the wall increases to infinity, thus normalisable
 * the wave function must be continuous
 * the derivative of the wave function must be continuous

Applications of electromagnetic cavities
Electrons which are trapped in an electromagnetic cavity are in a bound state and thus organise themselves as they do in a regular atom, thus expressing chemical-like behaviour. Several researchers have proposed to develop programmable matter by varying the number of trapped electrons in those cavities.

The discrete energy levels of electromagnetic cavities are exploited to produce photons of desired frequencies and thus are essential for nano- or submicrometre-scale laser devices.

title: Electromagnetic cavity


text:
Talk:A House for Mr Biswas

Title
Officially, it's "Mr", not "Mr.", in the title. Stan 12:27, 24 Jul 2004 (UTC)
 * Can anyone substantiate this? The library of congress, the bibliography on the Nobel prize website, and Amazon.com list the title as "Mr. Biswas." I can't find any support for "Mr Biswas."Wik-e-wik (talk) 18:40, 29 June 2009 (UTC)

Editions/publication date
Shouldn't the publication date refer to the first publication of the books (1961, Andre Deutsch)?

Also I don't see the point of the Editions section - it should either list all editions, or just in-print editions. At present it's unclear which of these it does. JSatyamurthy (talk) 04:27, 27 February 2008 (UTC)

 * I agree, so fixed...GrahamHardy (talk) 21:17, 24 May 2009 (UTC)

title: Talk:A House for Mr Biswas