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Talk:Calculus of constructions

Total
CoC can represent all functions provably total in higher-order logic, right? So, in what system is the strong normalization theory proved? Jim Apple 08:03, 19 August 2005 (UTC)
 * From the freely online accessible paper, I see no special care about this, even if the proof is not given. However, it does not seem that strong normalization is equivalent to consistency; they are both stated as corollaries of the same, rather technical theorem (whose proof is not included - the full reference given there is a PhD thesis in French). --Blaisorblade (talk) 01:14, 20 June 2008 (UTC)
 * Exаmine mу results, this is the extent of my earnings. 2A0D:3344:1402:E10:AB91:8D9F:819D:DCE (talk) 09:07, 20 July 2024 (UTC)

Deficiencies in the article
The inference rules presented in this article seem deficient. In particular, there is no way to prove anything of the form $${\Gamma \vdash x : M N}$$ from them. I imagine what's missing is a rule allowing one to derive $$x : A$$ from a derivation of $$x : B$$ and the beta-equality of $$A$$ and $$B$$, or something like that. Hopefully, someone more familiar with this material can clear things up. -Chinju 17:41, 2 November 2005 (UTC)
 * The online article (Coquand and Huet, 1986) states an obvious inference rule to prove typing for variables (they have the type declared in $$\Gamma$$), and states as a lemma (lemma 5 on page 7) that "if $${\Gamma \vdash M : N_1}$$ and $${\Gamma \vdash M : N_2}$$, then $${\Gamma \vdash N_1 : N_2}$$). I can't find the deduction rule you would like to have, but it should be surely a theorem, not a rule (even because typing judgements are introduced before conversion rules; conversion rules is the equivalent of beta-conversion in that article).--Blaisorblade (talk) 01:14, 20 June 2008 (UTC)
 * I retract my previous comment. The article has been changed significantly, and it now indeed includes a conversion typing rule, that is, "a rule allowing one to derive $$x : A$$ from a derivation of $$x : B$$ and the beta-equality of $$A$$ and $$B$$", as Chinju wrote. (It has the extra condition that $$A : K$$ for whatever technical reasons — but that might need a citation). I even misquoted Lemma 5 above: it should read $${\Gamma \vdash N_1 = N_2}$$. In the paper, the rule of conversion is the one asked for by Chinju, and does not need that side condition. However, that side condition is often needed (depending on the details of the formalization), for instance it is needed in pure type systems. --Blaisorblade (talk) 21:59, 10 August 2014 (UTC)

The whole article seem to miss many definitions or assume to get them from lambda calculus. When terms are defined, variables are not at all introduced. At a first look at the freely available paper, one sees no way to fully reconcile the article with the paper (in particular, it is not sufficient to assume that M and N are terms to form the term $$(\lambda x:M) N$$). The rules of conversion are omitted from the article; and so on. I'm marking this with the template.--Blaisorblade (talk) 00:46, 20 June 2008 (UTC)

A note: I know lambda-calculus and have read about Curry-Howard isomorphism, but I'm not at all an expert in the subject (particularly, in the calculus of constructions - I've just tried browsing the article to make sense of it). --Blaisorblade (talk) 01:14, 20 June 2008 (UTC)

Equiconsistency with ZFC
I removed the claim that the CoC was equiconsistent with ZFC because the paper cited ("Sets in types, types in sets") doesn't prove this. It uses a stronger type theory with inductive types, the calculus of inductive constructions. If ZFC[i] is ZFC with i inaccessible cardinals and CIC[i] is the calculus of inductive constructions with sorts Prop, Type1, ..., Typei, then the paper constructs a model of CIC[i] (plus choice and excluded middle axioms) in ZFC[i-1] and a model of ZFC[i] in CIC[i+2] (plus choice and excluded middle axioms.)  Spacepotato (talk) 03:17, 3 February 2022 (UTC)

Clarification needed for notation
What do the notations mean? The are not defined anywhere in the article. The-erinaceous-one (talk) 22:20, 24 February 2023 (UTC)
 * $$AB$$,
 * $$\lambda x: A . B$$, and
 * $$\forall x: A . B$$

 * They represent function application, lambda-abstraction, and dependent product formation, respectively. Spacepotato (talk) 19:24, 17 April 2023 (UTC)

On the page Lambda cube, the calculus of constructions uses the $$\Pi$$ operator instead of $$\forall$$. It's my understanding that the use of $$\forall$$ in, e.g. System F or Hindley–Milner, gets translated as $$\forall X.T[X] := \Pi_{X:\ast}.T[X]$$, i.e. "for all types X, T[X] is a type", so the $$\Pi$$ operator is more general. Does this need to be fixed, or is $$\forall$$ being used in a "punning" way? Metaweta (talk) 16:06, 24 May 2023 (UTC)
 * In this context, there is not much difference between $$\Pi$$ and $$\forall$$. You can use whichever you prefer. Spacepotato (talk) 17:35, 31 July 2023 (UTC)

Definition of "small" and "large" types
These terms are not defined on this page, nor anywhere else on Wikipedia as far as I can tell. They should either be defined or removed. Ablueberry87 (talk) 01:49, 6 January 2024 (UTC)

 * Bold 5.139.227.97 (talk) 11:56, 7 April 2024 (UTC)

title: Talk:Calculus of constructions


text:
Talk:Jo Mango

Untitled
I just thought I should say that I created this article and wasn't aware of the WP:MUSIC guidelines. I am (one of many) fans of the band and, to my knowledge, they don't know about this article's existence. I am sorry about this and now realize that I should not have started this article, but it is not the band's fault and there is no self promotion on their part.

Sorry again. I am a great fan of Wikipedia and would not intentionally do anything to undermine its policies.

- Emanekaf

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title: Talk:Jo Mango


text:
Wikipedia:Articles for deletion/Launie Anderssohn

 This page is an archive of the proposed deletion of the article below. Further comments should be made on the appropriate discussion page (such as the article's talk page or on a Votes for Undeletion nomination). No further edits should be made to this page.

The result of the debate was delete. Eugene van der Pijll 21:45, 26 August 2005 (UTC)

Launie Anderssohn
I suggested that this should get pitched along with The Dissonants, but it didn't; so I'm renominating it now. Non-notable band; gets just 46 Google hits and nothing on allmusic. Nomination withdrawn. Withdrawal withdrawn, because the sockpuppet-to-legitimate-vote ratio has gotten too high for comfort. Bearcat 19:44, 20 August 2005 (UTC)
 * Delete per above. (I live in the band's hometown & I've never heard of them). Dottore So 14:27, 19 August 2005 (UTC)
 * Unfortunately, I've heard of this band. They released an album last year, and the radio station that I work at received a promo copy (some idiot even called my show to request it).  As much as I'd like to see this tossed for personal reasons, I'm going to have to vote keep.  CJCurrie 19:37, 19 August 2005 (UTC)
 * CJ, I'm not sure that your reasons to keep are reasons that are acnowledged in WP:MUSIC. Correct me if I'm wrong, but it seems that your thinking is that since you've heard of them and they've released an album, then they are notable enough to be kept, which isn't the case. What's under contention as far as I can tell is whether they're non-notable or if having a member who was part of The Dears is enough to merit an encyclopedia article. --Blackcap | talk 19:05, August 24, 2005 (UTC)
 * The band is fairly well-known (or perhaps notorious) at the campus radio station where I work. In casting my vote, I extrapolated that other campus/community stations in Canada are probably familiar with this band as well.  In any case, I'm reluctant to delete a band that has released a full-length CD recording, and has distributed it to stations outside of their hometown (the worthlessness of their music notwithstanding).  The WP:Music guidelines only provide criteria for bands to be judged as indisputably notable; they don't cover all of the grey areas.  CJCurrie 19:08, 26 August 2005 (UTC)
 * Delete nn band vanity. -- Etacar11   03:31, 20 August 2005 (UTC)
 * Delete no Allmusic, no sign of meeting WP:MUSIC. --TheMidnighters 06:41, 20 August 2005 (UTC)
 * Delete. No evidence of notability provided by the article. Gamaliel 04:44, 23 August 2005 (UTC)

Votes from unregistered and very new users
'''Please note that Wikipedia has rules around how deletion votes are conducted. If voting on this page is your first-ever contribution to this site, your vote WILL NOT COUNT. The sockpuppetry is to stop NOW. Also, note that Wikipedia is not a directory of bands "trying to get a break". It's an encyclopedia; to be on here, a band has to already have gotten that big break.''' Bearcat 18:30, 23 August 2005 (UTC) keep - 70.49.202.51 02:30, 23 August 2005 (UTC) It seems to this Launie listner that all y'all haters out there are just scared. You're scared of the language they use and the feelings they give you at the tips of you pant pockets. But don't dismiss their importance in a sea of vastly unoriginal music and song lyrics. They are musicians and poets and lovers and future fathers and future lovers of each others kids. keep --204.50.131.2 21:31, 23 August 2005 (UTC)
 * For anyone who has never heard this band, let me tell you that they have some of the most original lyrics you will ever hear and blend it with an incredibly diverse range of music from country to rap funk and even calypso. They have toured 2 countries, and multiple outposts. A definite keeper. What a thrill it is to find them on this site. keep.--69.70.169.157 01:32, 23 August 2005 (UTC)
 * You and your friends can forget about this little game of yours; VfD votes by first-time users of the site are not counted. Bearcat 04:51, 23 August 2005 (UTC)
 * You could, however, improve the chances of keeping the article by improving it. Farquard 17:56, 23 August 2005 (UTC)
 * Of course if they have toured two countries then they fulfill another criterion for notablity (assuming those countries wern't, say, Barbados and Grenada). - Farquard 18:05, 23 August 2005 (UTC)
 * Launie Anderssohn rocked my socks off the first time I heard them. In addition to accomplished musicianship, these fun-loving fellas kept me smiling with their sometimes raunchy, always hilarious lyrics.
 * Launie Anderssohn is in the middle of changing the way music is played and listened to and appreciated. They are the best, or maybe second best, band in Montreal, no question.  While everyone else is regurgitating the same old crap over and over and being lauded as brilliant, Launie is creating some really incredible rock music with some really smart lyrics.  keep--24.203.43.147 04:41, 23 August 2005 (UTC)
 * Best band ever. No joke. Incisive, devicive, and inherently awesome. Keep your eyes open for this band, cuz they're gonna rock your underwear right outta your pants before you even know what happened. I could go on for days, but alas I must go. Do not delete this band, they should never be forgotten. keep (Unsigned vote by, first edit)
 * """keep""" --204.19.199.102 16:03, 23 August 2005 (UTC)
 * Harmless fun! What's the problem, young good guys from Montreal trying to get a break """keep"""--216.113.203.187 16:22, 23 August 2005 (UTC)
 * And this has exactly what bearing on whether they belong in an encyclopedia or not? Bearcat 22:05, 23 August 2005 (UTC)

this band rocks """keep"""--24.202.237.179 16:58, 24 August 2005 (UTC)
 * Keep Important band on the Montreal indie scene. On top of which, WP:MUSIC says that a band should be considered notable if one member was once part of an "extremely notable" band . - Farquard 19:28, 20 August 2005 (UTC)
 * User's second edit.
 * Like everyone and their brother they've played the Green Room, Barfly and Swimming. How is that notable?
 * Okay, I withdraw the nomination. I overlooked the Dears connection. If you're familiar with the band, though, could you expand the article a bit so it doesn't look so much like a deletion candidate? Bearcat 19:43, 20 August 2005 (UTC)
 * When did The Dears become extremely notable? The Dears are notable, but not extremely so, therefore every single band each member has ever been with or will be with is not necessarily notable, especially if they don't meet any of the other guidelines. --TheMidnighters 09:41, 21 August 2005 (UTC)
 * Can you actually quantify the line where one can realistically mark a clear division between "notable" and "extremely notable"? I sure as hell can't...to me, the line is contextually relative to the genre in which the band operates, rather than an objective scale that ranks all bands by the same measure. They're no match for the notability of The Beatles, granted, but within the specific context of indie rock in the 2000s, The Dears can certainly be described as "extremely notable". Bearcat 18:04, 22 August 2005 (UTC)
 * If a band has widespread popularity like the Beatles, then a side project (like George Harrison's solo work) is worthy of an encyclopedia. If a band doesn't have that, (as in the case of the Dears, having put out a few albums but, as far as I can tell, not know very much outside of Quebec), then while they themselves may warrant an encyclopedia article, their side projects may not. Anyway, in the realm of, say, Star Trek fandom, obscure bits on machinery might be considered notable, but would never make its way into an encyclopedia because it's too irrelevant to most people. This seems like music's version of that. It just doesn't hit enough points in WP:MUSIC to warrant staying. From going on their web site, they don't even seem to have a record label, saying only that you can get their music at Le Subalterne, a local record shop. They're a band who has one semi-notable person and nothing else. Maybe a good band, but not something for Wikipedia. Delete. --Blackcap | talk 17:32, August 24, 2005 (UTC)
 * To put it more simply, I think TheMidnighters' comment above says all it needs to. --Blackcap | talk 19:09, August 24, 2005 (UTC)

The Dears are considered "extremely notable" across Canada having had a near-cult following on many college campuses for years. There is no better guage for "notable" in indie-rock's transient and poor-student-driven world. Launie Anderssohn are genre groundbreakers misunderstood by the dull, and celebrated by intelligent witty townsfolk and hard to thrill musicians alike. As in, they have their own sound and message and media package. As in, they are influential. The fact that they play at smaller clubs should not make them less noteworthy for the history of musical progress. Wikipedia is a boon to music writers everywhere, let's keep it that way. The article should be expanded to contextualize them more distinctly """keep""" --24.80.81.229 06:50, 26 August 2005 (UTC)
 * Proof by "because I said so". Can you show independent web references (newspaper articles, coverage or chart placement in Chart or exclaim!, etc.) which prove that they're notable? If not, they belong on skwik, not here. Bearcat 17:41, 26 August 2005 (UTC)
 * The above discussion is preserved as an archive of the debate. Please do not modify it. Subsequent comments should be made on the appropriate discussion page (such as the article's talk page or in an undeletion request). No further edits should be made to this page.


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DNA mismatch repair

DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage.

Mismatch repair is strand-specific. During DNA synthesis the newly synthesised (daughter) strand will commonly include errors. In order to begin repair, the mismatch repair machinery distinguishes the newly synthesised strand from the template (parental). In gram-negative bacteria, transient hemimethylation distinguishes the strands (the parental is methylated and daughter is not). However, in other prokaryotes and eukaryotes, the exact mechanism is not clear. It is suspected that, in eukaryotes, newly synthesized lagging-strand DNA transiently contains nicks (before being sealed by DNA ligase) and provides a signal that directs mismatch proofreading systems to the appropriate strand. This implies that these nicks must be present in the leading strand, and evidence for this has recently been found. Recent work has shown that nicks are sites for RFC-dependent loading of the replication sliding clamp, proliferating cell nuclear antigen (PCNA), in an orientation-specific manner, such that one face of the donut-shape protein is juxtaposed toward the 3'-OH end at the nick. Loaded PCNA then directs the action of the MutLalpha endonuclease to the daughter strand in the presence of a mismatch and MutSalpha or MutSbeta.

Any mutational event that disrupts the superhelical structure of DNA carries with it the potential to compromise the genetic stability of a cell. The fact that the damage detection and repair systems are as complex as the replication machinery itself highlights the importance evolution has attached to DNA fidelity.

Examples of mismatched bases include a G/T or A/C pairing (see DNA repair). Mismatches are commonly due to tautomerization of bases during DNA replication. The damage is repaired by recognition of the deformity caused by the mismatch, determining the template and non-template strand, and excising the wrongly incorporated base and replacing it with the correct nucleotide. The removal process involves more than just the mismatched nucleotide itself. A few or up to thousands of base pairs of the newly synthesized DNA strand can be removed.

Mismatch repair proteins
Mismatch repair is a highly conserved process from prokaryotes to eukaryotes. The first evidence for mismatch repair was obtained from S. pneumoniae (the hexA and hexB genes). Subsequent work on E. coli has identified a number of genes that, when mutationally inactivated, cause hypermutable strains. The gene products are, therefore, called the "Mut" proteins, and are the major active components of the mismatch repair system. Three of these proteins are essential in detecting the mismatch and directing repair machinery to it: MutS, MutH and MutL (MutS is a homologue of HexA and MutL of HexB).

MutS forms a dimer (MutS2) that recognises the mismatched base on the daughter strand and binds the mutated DNA. MutH binds at hemimethylated sites along the daughter DNA, but its action is latent, being activated only upon contact by a MutL dimer (MutL2), which binds the MutS-DNA complex and acts as a mediator between MutS2 and MutH, activating the latter. The DNA is looped out to search for the nearest d(GATC) methylation site to the mismatch, which could be up to 1 kb away. Upon activation by the MutS-DNA complex, MutH nicks the daughter strand near the hemimethylated site. MutL recruits UvrD helicase (DNA Helicase II) to separate the two strands with a specific 3' to 5' polarity. The entire MutSHL complex then slides along the DNA in the direction of the mismatch, liberating the strand to be excised as it goes. An exonuclease trails the complex and digests the ss-DNA tail. The exonuclease recruited is dependent on which side of the mismatch MutH incises the strand – 5' or 3'. If the nick made by MutH is on the 5' end of the mismatch, either RecJ or ExoVII (both 5' to 3' exonucleases) is used. If, however, the nick is on the 3' end of the mismatch, ExoI (a 3' to 5' enzyme) is used.

The entire process ends past the mismatch site - i.e., both the site itself and its surrounding nucleotides are fully excised. The single-strand gap created by the exonuclease can then be repaired by DNA Polymerase III (assisted by single-strand-binding protein), which uses the other strand as a template, and finally sealed by DNA ligase. DNA methylase then rapidly methylates the daughter strand.

MutS homologs
When bound, the MutS2 dimer bends the DNA helix and shields approximately 20 base pairs. It has weak ATPase activity, and binding of ATP leads to the formation of tertiary structures on the surface of the molecule. The crystal structure of MutS reveals that it is exceptionally asymmetric, and, while its active conformation is a dimer, only one of the two halves interacts with the mismatch site.

In eukaryotes, M ut S h omologs form two major heterodimers: Msh2/Msh6 (MutSα) and Msh2/Msh3 (MutSβ). The MutSα pathway is involved primarily in base substitution and small-loop mismatch repair. The MutSβ pathway is also involved in small-loop repair, in addition to large-loop (~10 nucleotide loops) repair. However, MutSβ does not repair base substitutions.

MutL homologs
MutL also has weak ATPase activity (it uses ATP for purposes of movement). It forms a complex with MutS and MutH, increasing the MutS footprint on the DNA.

However, the processivity (the distance the enzyme can move along the DNA before dissociating) of UvrD is only ~40–50 bp. Because the distance between the nick created by MutH and the mismatch can average ~600 bp, if there is not another UvrD loaded the unwound section is then free to re-anneal to its complementary strand, forcing the process to start over. However, when assisted by MutL, the rate of UvrD loading is greatly increased. While the processivity (and ATP utilisation) of the individual UvrD molecules remains the same, the total effect on the DNA is boosted considerably; the DNA has no chance to re-anneal, as each UvrD unwinds 40-50 bp of DNA, dissociates, and then is immediately replaced by another UvrD, repeating the process. This exposes large sections of DNA to exonuclease digestion, allowing for quick excision (and later replacement) of the incorrect DNA.

Eukaryotes have five M ut L h omologs designated as MLH1, MLH2, MLH3, PMS1, and PMS2. They form heterodimers that mimic MutL in E. coli. The human homologs of prokaryotic MutL form three complexes referred to as MutLα, MutLβ, and MutLγ. The MutLα complex is made of MLH1 and PMS2 subunits, the MutLβ heterodimer is made of MLH1 and PMS1, whereas MutLγ is made of MLH1 and MLH3. MutLα acts as an endonuclease that introduces strand breaks in the daughter strand upon activation by mismatch and other required proteins, MutSα and PCNA. These strand interruptions serve as entry points for an exonuclease activity that removes mismatched DNA. Roles played by MutLβ and MutLγ in mismatch repair are less-understood.

MutH: an endonuclease present in E. coli and Salmonella
MutH is a very weak endonuclease that is activated once bound to MutL (which itself is bound to MutS). It nicks unmethylated DNA and the unmethylated strand of hemimethylated DNA but does not nick fully methylated DNA. Experiments have shown that mismatch repair is random if neither strand is methylated. These behaviours led to the proposal that MutH determines which strand contains the mismatch. MutH has no eukaryotic homolog. Its endonuclease function is taken up by MutL homologs, which have some specialized 5'-3' exonuclease activity. The strand bias for removing mismatches from the newly synthesized daughter strand in eukaryotes may be provided by the free 3' ends of Okazaki fragments in the new strand created during replication.

PCNA β-sliding clamp
PCNA and the β-sliding clamp associate with MutSα/β and MutS, respectively. Although initial reports suggested that the PCNA-MutSα complex may enhance mismatch recognition, it has been recently demonstrated that there is no apparent change in affinity of MutSα for a mismatch in the presence or absence of PCNA. Furthermore, mutants of MutSα that are unable to interact with PCNA in vitro exhibit the capacity to carry out mismatch recognition and mismatch excision to near wild type levels. Such mutants are defective in the repair reaction directed by a 5' strand break, suggesting for the first time MutSα function in a post-excision step of the reaction.

Inherited defects in mismatch repair
Mutations in the human homologues of the Mut proteins affect genomic stability, which can result in microsatellite instability (MSI), implicated in some human cancers. In specific, the hereditary nonpolyposis colorectal cancers (HNPCC or Lynch syndrome) are attributed to damaging germline variants in the genes encoding the MutS and MutL homologues MSH2 and MLH1 respectively, which are thus classified as tumour suppressor genes. One subtype of HNPCC, the Muir-Torre Syndrome (MTS), is associated with skin tumors. If both inherited copies (alleles) of a MMR gene bear damaging genetic variants, this results in a very rare and severe condition: the mismatch repair cancer syndrome (or constitutional mismatch repair deficiency, CMMR-D), manifesting as multiple occurrences of tumors at an early age, often colon and brain tumors.

Epigenetic silencing of mismatch repair genes
Sporadic cancers with a DNA repair deficiency only rarely have a mutation in a DNA repair gene, but they instead tend to have epigenetic alterations such as promoter methylation that inhibit DNA repair gene expression. About 13% of colorectal cancers are deficient in DNA mismatch repair, commonly due to loss of MLH1 (9.8%), or sometimes MSH2, MSH6 or PMS2 (all ≤1.5%). For most MLH1-deficient sporadic colorectal cancers, the deficiency was due to MLH1 promoter methylation. Other cancer types have higher frequencies of MLH1 loss (see table below), which are again largely a result of methylation of the promoter of the MLH1 gene. A different epigenetic mechanism underlying MMR deficiencies might involve over-expression of a microRNA, for example miR-155 levels inversely correlate with expression of MLH1 or MSH2 in colorectal cancer.

MMR failures in field defects
A field defect (field cancerization) is an area of epithelium that has been preconditioned by epigenetic or genetic changes, predisposing it towards development of cancer. As pointed out by Rubin " ...there is evidence that more than 80% of the somatic mutations found in mutator phenotype human colorectal tumors occur before the onset of terminal clonal expansion." Similarly, Vogelstein et al. point out that more than half of somatic mutations identified in tumors occurred in a pre-neoplastic phase (in a field defect), during growth of apparently normal cells.

MLH1 deficiencies were common in the field defects (histologically normal tissues) surrounding tumors; see Table above. Epigenetically silenced or mutated MLH1 would likely not confer a selective advantage upon a stem cell, however, it would cause increased mutation rates, and one or more of the mutated genes may provide the cell with a selective advantage. The deficientMLH1 gene could then be carried along as a selectively near-neutral passenger (hitch-hiker) gene when the mutated stem cell generates an expanded clone. The continued presence of a clone with an epigenetically repressed MLH1 would continue to generate further mutations, some of which could produce a tumor.

MSI and immune checkpoint blockade response
MMR and mismatch repair mutations were initially observed to associate with immune checkpoint blockade efficacy in a study examining responders to anti-PD1. The association between MSI positivity and positive response to anti-PD1 was subsequently validated in a prospective clinical trial and approved by the FDA.

MMR components in humans
In humans, seven DNA mismatch repair (MMR) proteins (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1 and PMS2) work coordinately in sequential steps to initiate repair of DNA mismatches. In addition, there are Exo1-dependent and Exo1-independent MMR subpathways.

Other gene products involved in mismatch repair (subsequent to initiation by MMR genes) in humans include DNA polymerase delta, PCNA, RPA, HMGB1, RFC and DNA ligase I, plus histone and chromatin modifying factors.

In certain circumstances, the MMR pathway may recruit an error-prone DNA polymerase eta (POLH). This happens in B-lymphocytes during somatic hypermutation, where POLH is used to introduce genetic variation into antibody genes. However, this error-prone MMR pathway may be triggered in other types of human cells upon exposure to genotoxins and indeed it is broadly active in various human cancers, causing mutations that bear a signature of POLH activity.

MMR and mutation frequency
Recognizing and repairing mismatches and indels is important for cells because failure to do so results in microsatellite instability (MSI) and an elevated spontaneous mutation rate (mutator phenotype). In comparison to other cancer types, MMR-deficient (MSI) cancer has a very high frequency of mutations, close to melanoma and lung cancer, cancer types caused by much exposure to UV radiation and mutagenic chemicals.

In addition to a very high mutation burden, MMR deficiencies result in an unusual distribution of somatic mutations across the human genome: this suggests that MMR preferentially protects the gene-rich, early-replicating euchromatic regions. In contrast, the gene-poor, late-replicating heterochromatic genome regions exhibit high mutation rates in many human tumors.

The histone modification H3K36me3, an epigenetic mark of active chromatin, has the ability to recruit the MSH2-MSH6 (hMutSα) complex. Consistently, regions of the human genome with high levels of H3K36me3 accumulate less mutations due to MMR activity.

Loss of multiple DNA repair pathways in tumors
Lack of MMR often occurs in coordination with loss of other DNA repair genes. For example, MMR genes MLH1 and MLH3 as well as 11 other DNA repair genes (such as MGMT and many NER pathway genes) were significantly down-regulated in lower grade as well as in higher grade astrocytomas, in contrast to normal brain tissue. Moreover, MLH1 and MGMT expression was closely correlated in 135 specimens of gastric cancer and loss of MLH1 and MGMT appeared to be synchronously accelerated during tumor progression.

Deficient expression of multiple DNA repair genes is often found in cancers, and may contribute to the thousands of mutations usually found in cancers (see Mutation frequencies in cancers).

Aging
A popular idea, that has failed to gain significant experimental support, is the idea that mutation, as distinct from DNA damage, is the primary cause of aging. Mice defective in the mutL homolog Pms2 have about a 100-fold elevated mutation frequency in all tissues, but do not appear to age more rapidly. These mice display mostly normal development and life, except for early onset carcinogenesis and male infertility.

title: DNA mismatch repair


text: User:Tijuana Brass

title: User:Tijuana Brass


text:
ORTF stereo technique

The ORTF stereo technique, also known as side-other-side, is a microphone technique used to record stereo sound. It was devised around 1960 at the now-defunct Office de Radiodiffusion Télévision Française (ORTF).

This technique combines both the volume difference and the timing difference as sound arrives on- and off-axis at two cardioid microphones spread to a 110° angle, and spaced 17 cm apart.

The microphones should be as similar as possible, preferably a frequency-matched pair of an identical type and model.

The result is a realistic stereo field that has reasonable compatibility with mono playback. Since the cardioid polar pattern rejects off-axis sound, less of the ambient room characteristics are picked up. This means that the mics can be placed farther away from the sound sources, resulting in a blend that may be more appealing. Further, the availability of purpose-built microphone mounts makes ORTF easy to achieve.

As with all microphone arrangements, the spacing and angle can be manually adjusted slightly by ear for the best sound, which may vary depending on room acoustics, source characteristics, and other factors. But this arrangement is defined as it is because it was the result of considerable research and experimentation, and its results are predictable and repeatable.

These interchannel differences are not the same as interaural differences, as produced by artificial head recordings. Even the spacing of 17 cm is not strictly based on interaural ear spacing. The recording angle for this microphone system is ±48° = 96°.

title: ORTF stereo technique


text: Template:City building series

title: Template:City building series


text:
Words Worth

Words Worth (ワーズ･ワース) is a Japanese adult role-playing video game originally released for NEC PC-98 computer systems, and remade for Microsoft Windows. The game's story is linear, with only one story decision near the end, leading to one of five different endings.

A five-part animated erotic direct-to-video series was adapted from the game's story. It also has a side story series, Words Worth Gaiden (ワーズ・ワース外伝) (known as Words Worth Outer Stories in the English release). The anime has the same general story, but the anime cuts out several characters and changes the plot mostly to create more sex scenes. The English dub is notable for featuring real life porn actresses Jenna Jameson and Nikki Dial. The rest of the English cast remained uncredited.

Gameplay
The gameplay of Words Worth is similar to other fantasy games of the era such as The Elder Scrolls II: Daggerfall but with a tongue and cheek sexual undertone. It is a remake of the 1993 game of the same name and while the plot is near identical, the graphics, gameplay, and visuals have been greatly improved.

Words Worth is primarily a first-person dungeon crawler. Even though there are a few "friendly" areas, such as the hero Astro's bedroom and a town where the hero can rest and buy supplies, most of the game is spent in dungeon-like, maze-like areas (with an auto-map feature). There is no party in the game: Astro has to face the enemies alone. The enemies appear randomly. The 1999 remake has the players to click on the enemies to slash them and the combat is turn-based. The game has scenes with nudity and sexual situations.

Like most fantasy role playing games Words Worth has lots of focus on story and narrative plot points but unlike many contemporaries in the fantasy genre Words Worth is entirely voice acted. As the players play as a young hero trying to prove himself worthy while surrounded by vixens, the game falls into the style of many Japanese anime plots where a young awkward protagonist is surrounded by sexpot girls.

Plot
The skill of sword-fighting is known to two tribes, the Tribes of Light (which consists of humans living on the world's surface) and Shadow (largely part-human-part-animal creatures and monsters living in an underground city, who enjoy a lifespan five times as long as the Tribe of Light and age one-fifth as quickly). The two tribes lived in peace and harmony, their domains separated by the "Words Worth" tablet—a huge monolith slab erected by an almighty creator. Although the tablet has writing on it, neither Tribe can read the text. One day, Words Worth was mysteriously destroyed by an unknown entity; its fragments were scattered among the domain of the Tribes of Shadow. The two Tribes blamed each other for the tablet's destruction, and started a war that has continued for 150 years (100 in the anime). Astral, prince of the Tribe of Shadow, desires to become a Swordsman of Shadow, but his father, King Wortoshika, forbids him to do so. He is engaged to Sharon, a beautiful swordswoman and Astral's childhood friend, who has feelings for Astral but wishes he were stronger.

Tribe of Shadow

 * Astral: Prince of the Shadow realm, and heir to King Wortoshika. His name is based on Castor and is changed to 'Esterla' in the Media Blasters translation. He is a generic good-natured-but-oblivious video game protagonist who gains more experience over the course of the game. In the second half of the story, he is given the alias Pollux. In the anime, his character is more developed, being a natural swordsman who is also undisciplined and self-conscious (especially where his fiancée Sharon is concerned), and low on sexual morals. In both versions, he is eventually revealed to be the lost son of the legendary Light swordsman Pollux, after whom he was nicknamed because of his likeness with him. Voice actor: Kenichi Suzumura (credited as Ken Sozomura)

 * Sharon: One of the two most formidable officers (along with Kaiser) of the Shadow Realm army and a lifelong friend of Astral's. She is beautiful, but stern and commanding. Sharon is engaged to Astral, but is only attracted to men who are stronger than her in combat; she gradually falls in love with him as he proves his competence. The DOS version of the game included a sex scene with Sharon, but this was cut out in the Win95 edition. One of the game endings has Astral together with Sharon. In the Media Blasters translation, she is named Shalom. Voice actor: Rie Nakamizu

 * Nina: A catgirl who issues swordsman's licenses in the Shadow realm, and mother of Ariadne in the second half of the game. She has a secret crush on Astral. For many fans, she is the most-liked character in the series, likely due to her actions during the second half of the game. The DOS version of Nina was a clear parody of Lum, but her character was completely redesigned for the Win95 version. One of the game endings has Astral together with Nina. Voice actor: Emi Motoi (credited as Emi Nakano)

 * Kaiser: His name is the German word for 'emperor'. One of the two most formidable Shadow swordsmen, his pride and desire to win Sharon's heart often place him at odds with Astral. In the game, he attempts to seduce Sharon while she is under the influence of an aphrodisiac-poisoned wound caused by Fabris; in the anime, she more openly rejects his advances. In the game, he begins living with Sharon during the Miyu, Nina, and Delta's endings. Kaiser is renamed 'Caesar' in both official translations of the anime. Voice actor: Jōichi Sawada

 * Wortoshika: A large, muscular blue-skinned man, he is King of the Shadow tribe. His name could be a corruption of the term 'Wordseeker' due to the Japanese pronunciation. He is fiercely overprotective of his son. While ruthless and practical, he also has an honorable side. Voice actor: Takashi Tokorozawa

 * Tessio: Chief advisor to Wortoshika. Along with his Light counterpart, Menza, he is part of an evil entity which actually has caused the war between the two tribes. In the anime, they are aware of this, whereas in the game they are unwitting aspects of the dark entity. His name is based on Salvatore Tessio, and his look is based on Peter Clemenza; the opposite is true for Menza. Voice actor: Soichi Nagashima

 * Stallion: A lecherous half-horse, half-human officer of the Shadow tribe army. He believes that "women from the Tribe of Light are more attractive", and often takes female prisoners to a torture chamber to rape them. He is most famous in an internet meme for the quote, "Your resistance only makes my penis harder!" In the series' subsequent omake, he is seen marrying Eoria; this detail is briefly mentioned in all five of the game's endings. In the game, he has grown an incongruous white mustache in the second half. Voice actor: Shinya Furumoto

 * Hyde: A young Elf of the Shadow Tribe and Astral's best friend. Despite being a licensed swordsman, he is very timid and cowardly, and thus is ashamed of himself. In the game, he dies after succumbing to one of Club's machines; in the anime, he is slain by Sir Fabris after trying to stop him from raping Sharon. In both cases, his death affects Astral greatly.

 * Katra: A living, willful Skeleton Warrior and officer in the Shadow tribe army, he serves as a soldier and at times a messenger. Voice actor: Utako

 * Delta: A woman with gray, painted skin and bat wings, possibly a succubus. In the game, she only appears in the second half, and seems to often get stuck in erotic situations. In the anime, her curiosity gets the better of her when she follows Tessio and Menza, and is subsequently raped and hypnotized to serve the two in a plot against Astral. One of the game endings has Astral together with Delta (this was added in the Win95 edition); she marries Rigel if the player chooses Sharon's, Nina's, or Miyu's endings. Voice actor: Tsutomu Takashima (OVA) / Ben Takada (game)

 * Ariadne: Nina's and Astral's daughter. She only appears in the second half of the game. Uniting the blood from both the Light and Shadow Tribes, she ultimately plays the most vital role in reuniting the two tribes. Voice actor: Yoshino Kawayama

 * Carrot: A small fairy which can control monsters much larger than her. Appears in the second half of the game only, in which she is captured and molested by William, and marries Rigel during Delta's ending. She has a small cameo appearance in the anime's omake episode at Stallion's and Eoria's wedding.

 * Weiss: A friendly old person who dispenses advice to Astral. Weiss is male in the DOS version, female in the Win95 version, and does not appear in the anime.

Tribe of Light

 * Pollux: At the end of the first half of the game, Maria blasts Astral 20 years forward into the future, where he grows a beard and loses all memory of who he was. Eventually, he adopts the identity Pollux (named after a legendary swordsman whom he resembles) and fights for the Tribe of Light. In the game, he doesn't regain his memories until very near the end of the story, whereas in the anime he regains them much earlier. Voice actor: Aihime Yoshida

 * Pollux (Sr.): A famous swordsman of the Tribe of Light, said to have died of illness but was in fact murdered, leading to his wife committing suicide. He had two children, a boy and a girl, who vanished after the attack. In the anime, it is revealed that Astral is his lost son, while the game also implies that Maria was the baby girl. The anime hints that he was killed by Wortoshika, while in the game, the combined form of Tessio and Menza was the culprit.

 * Miyu: A novice sorceress, daughter of Maria, and initially William's fiancé. She is named Mew in the NuTech translation and Mu in the game's fan-translation, and only appears in the second half of the game. Her life is saved by Pollux and slowly develops feelings for him. One of the game endings has Astral together with Miyu; in the Nina, Sharon and Delta endings she marries William. There are some indications that she actually might be Astral's niece (Maria and Astral are hinted to be siblings in the game) or daughter (from his raping her mother in the anime), and as a result a sexual relationship between them would be incestuous. Voice actor: Naoko Takano (credited as Mirei Yamano)

 * Maria: A sorceress, daughter of King Fabris, and mother of Miyu in the second half of the game, where she prefers to teleport enemies away rather than fight them. In the anime, she is raped by Astral after he falls into her prison cell. In the game, she is only an adopted child of Fabris, her biological parents being hinted to be the original Pollux and Maria, making her Astral's sister. Voice actor: Mimi Yamano

 * Maria (Sr.): Wife of the original Pollux, who threw herself into a lake along with her baby girl after her husband's death and her son's disappearance. She is biological mother of Astral and, in the game, Maria. Her magic ring was passed down to Maria and later on to Miyu.

 * Fabris: An older and more experienced knight, stronger than both Kaiser and Sharon. He is revealed at the end of the first half to be the (adoptive) father of Maria and king of the Tribe of Light, shortly after Astral severs his right arm. In both versions of events, he lusts over Sharon after seeing her fight, actively attempting to rape her in the anime and coating one of his daggers with an aphrodisiac—which successfully injures Sharon—in the game. He is named Fabrees in the Media Blasters translation. Voice actor: Ikuya Fujiki

 * Menza: Chief advisor to Fabris. Along with his Shadow counterpart, Tessio, he is part of an evil entity which actually has caused the war between the two tribes. In the anime, they are aware of this, whereas in the game, they are unwitting aspects of the dark entity. His name is based on Peter Clemenza, and his look is based on Salvatore Tessio—the opposite is true for Tessio.

 * Epo: A blue-haired swordswoman, named April in the fan-translation and Media Blasters translation. In the game, she is forced to strip by Astral and starts bawling (which scares Astral away); 20 years later, in the second half of the game, she becomes a shopkeeper in town. The DOS version of Epo is a parody of Nadia from Nadia: The Secret of Blue Water, but her character was completely redesigned for the Win95 version. Epo has a small cameo appearance in the anime series as a stall owner, but is one of the main characters in the Gaiden anime, where it documents her adventures which lead her to conclude that the life of a swordswoman was not for her. She gets lost in the realm of the Shadow tribe and runs into monsters who sexually assaulted her at every turn. Her final monster encounter was Stallion, who begins molesting her, but is interrupted when Astral falls from a cliff and knocks Stallion into the water. Epo, still aroused by the sensations of Stallion's treatment of her, invites Astral to take her virginity.

 * Sabrina: A dark-skinned, taciturn female knight, Sabrina is tortured, interrogated, and molested when she is captured by the Tribe of Shadows. She is strong-willed and would do nearly anything to destroy the enemy Tribe of Shadows. In the second half of the game, she becomes the mother of Rita. She also appears in the Gaiden anime, where she is Persia's dominant lesbian lover.

 * Rita: A dark-skinned Light tribe swordswoman, and daughter of Sabrina who appears in the game's second half only. In the game, she is timid and reluctant to fight. At some point, she gets her posterior trapped in a hole in the ground; Pollux notices it in the ceiling and attempts to attack it. Later on, he jokingly calls her "butt-girl". In the anime, she is much more outgoing, and has a chance encounter with Wortoshika. Rita attempts to defeat him in the name of the Tribe of Light, but finds that he is too powerful and states that a death by him would be an honorable one. Instead, Wortoshika attempts to procreate in order to produce an heir following Astral's disappearance. It is implied that during this encounter, Rita and Wortoshika develop strong feelings for one another; Wortoshika offers her a home in the Shadow Tribe if the Tribe of Light refuses to take her back, and Rita sheds tears of anguish when Wortoshika later dies in the anime. Voice actor: Chiyo

 * Persia: Servant and student of Sabrina who does not appear to enjoy sword-fighting. She is an adolescent in the game, but a juvenile adult in the Gaiden anime, where she has sexual encounters with both Astral and Sabrina.

 * Silvanna: A tomboyish fencer, possibly a cousin of Maria. She is named Silverna in the NuTech translation. In the game, she is captured and raped by Stallion. In the second half, she is the mother of Eoria. In the anime, she was captured along with Maria during the initial encounter with the Tribe of Shadow and is molested by two pig guards; Maria comes to her rescue before they can go through with their plans to gang-rape her.

 * Eoria: Daughter of Silvanna, whom she strongly resembles in both appearance and personality. She appears only in the second half of the game. Stallion attempts to rape her in the second half by giving her an aphrodisiac, but Pollux stops Stallion and as a result, Eoria comes on to Pollux instead, snapping out of the drug-induced trance in mid-kiss. In an omake of the anime series, she is shown marrying Stallion, a detail mentioned in all five of the game's endings.

 * Bellabella: A nymphomaniac sorceress who uses magic mushrooms for both magical and sexual purposes, and because of this appears to age very slowly (having exactly the same appearance in the second half of the story 20 years later). She is one of the two characters who is shown to have actual sexual intercourse with Astral in the game (the other being Nina). She is named Belladonna in the game's fan translation and does not appear in the anime.

 * Club: A master trap-maker, he is named Kaleb in the fan-translation. In the game, he is one of the initial party to get captured by the Shadow Tribe (along with Fabris, Dark, Silvanna, Sabrina, and Maria), and later kills Hyde. In the anime, he has a very small unnamed appearance, piloting one of his war machines. Voice actor: Akio Suyama

 * Dark: A fearless and brave swordswoman. In the second half, she is the mother of Vega. She does not appear in the anime and is renamed Arkia in the fan-translation.

 * Norman: A somewhat pretentious swordsman, he has a power move that parodies the kamehameha from Dragon Ball. Boyfriend of Epo, he is later killed by Astral. Norman makes a small appearance in the Gaiden anime as the injured boyfriend of Epo who attempts to find her when she falls in the river and gets lost.

 * Vega: Daughter of Dark, she appears only in the second half of the game. Vega often contemplates finding a boyfriend and starting a family. In the DOS version, she is a swordswoman who has a sexual encounter with Pollux; in the Win95 version, she is an archer and has no such encounter. She has a small cameo appearance in the anime's omake episode at Stallion's and Eoria's wedding.

 * Algol: A cowardly swordsman who is very greedy and attracted to gold. He has a habit of calling people by absurd names and appears in the second half of the game. In all of the game's endings, he marries one of the four unnamed female shopkeepers (though which one is never specified). Algol is not present in the anime.

 * Rigel: A dark-skinned lecherous swordsman, Rigel appears in the second half of the game. He believes that "women from the Tribe of Shadow are more attractive", making him somewhat of a counterpart to Stallion. In fact, he and Stallion fight over Delta at one point. Rigel makes a very brief cameo appearance in the anime. He marries Carrot in the Delta and harem endings, and Delta herself in all others.

 * William: Son of Fabris, and fiancé of Miyu, he appears as a very young child standing up to Astral in the first half; 20 years later, he has "matured" into a cowardly swordsman who seizes credit for Pollux's achievements. William occasionally displays pedophilic tendencies (as evidenced by his treatment of Carrot).

Words Worth no Hitobito
Words Worth no Hitobito (ワーズ・ワースの人々) is a cross-over between Words Worth and The Mystery of Nonomura Hospital. In the first half of the game, Umihara, the main protagonist of The Mystery of Nonomura Hospital, enters the world of Words Worth as summoned by Wortoshika. The game takes place in the intervening 20 years between Astral's disappearance and reappearance. In the second half, Sharon from Words Worth comes into the world of Nonomura Hospital and has a sexual affair with Umihara.

Release history
The original video game was made by ELF Corporation in 1993. The game was remade for Windows 95 in 1999, with some changed character designs, full-voice added to the supporting characters, 3D polygon graphics, and an opening animation sequence. That same year, the anime adaptation was also released. The series was originally released in English by NuTech Digital in 1999, but the license was lost due to NuTech being sued for failure to pay royalties. According to AnimeNation, that license was awarded in 2007 to Media Blasters, which released the series under Kitty Media.

The Canada Border Services Agency ruled in 2007 that Words Worth is obscene under subsection 163(8) of the Criminal Code and is prohibited from being brought into the country.

In 2003, Words Worth was released in German by Trimax as Am Ende des Lichtes (At the End of the Light). Trimax also released Words Worth Gaiden in 2009 as Die Kriegerinnen des Lichts (The She-Warriors of Light).

Special episodes (2002–2009)
The series spawned two additional Gaiden OVA episodes and one comedic Omake episode. The Gaiden episodes take place in the final third of the episode "Pantheon of Play", the Omake following the conclusion of the original series.

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Talk:Craig Benson

Untitled
Article seems slanted toward the POV of Benson's critics and limited in discussion of Benson's own politics and initiatives. Needs more fleshing out. — Preceding unsigned comment added by Bcarlson33 (talk • contribs) 08:11, 19 August 2005 (UTC)

 * He was only in office two years and by the time he was defeated, even many Republicans were highly critical of him. I'm not sure how many positive accomplishments he had, or how many political iniatives he managed to push through. --JamesB3 08:48, 19 August 2005 (UTC)

 * That may be true, but if so it should be added to the article. As it is the article only focuses on the "lowlights" of his public career (lawsuit, Pepin scandal, etc.) -- BCarlson33 August 19th 2005

Factual errors
There are factual errors on this page and clearly it is biased against Benson. There should be more about his MANY accomplishments as Governor. — Preceding unsigned comment added by RepHerman (talk • contribs) 14:07, 20 January 2006 (UTC)

 * Actually, as far as I'm concerned there hasn't been one New Hampshire governor, Republican or Democrat, since I've lived here that has accomplished a whole lot. I don't think this is because they are bad governors, but rather because of the limited 2-year terms that they are given. In Benson's case, he didn't have time to accomplish anything significant... and if current Governor John Lynch isn't re-elected it will likely be a similair story there. --Prezboy1 14:18, 11 July 2006 (UTC)

 * Benson wasnt very good but you shouldn't eliminate what people say on the discussion of craig. 04:49, 31 December 2006 (UTC)24.2.155.207

 * Bensons career was one lowlight. He was horrific. How about that white SUV incident in December 2004? Have some class and don't erase my opinon on a TALK PAGE. - 21:10, 22 March 2007 (UTC)24.2.155.207

 * Odd - are you going to come back and complain every three months, regardless of whether anybody is listening? Anyway, I erased a comment of yours several months ago not because it was a content-free insult (like the above comment) but because it was an obscene content-free insult. These Talk pages are for discussions of articles, not rants about politicians. - DavidWBrooks 11:39, 23 March 2007 (UTC)

 * Odd...have some class Davie! — Preceding unsigned comment added by 24.2.155.207 (talk) 01:42, 24 March 2007 (UTC)

Copyright problem removed
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Base excision repair

Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from the genome. The related nucleotide excision repair pathway repairs bulky helix-distorting lesions. BER is important for removing damaged bases that could otherwise cause mutations by mispairing or lead to breaks in DNA during replication. BER is initiated by DNA glycosylases, which recognize and remove specific damaged or inappropriate bases, forming AP sites. These are then cleaved by an AP endonuclease. The resulting single-strand break can then be processed by either short-patch (where a single nucleotide is replaced) or long-patch BER (where 2–10 new nucleotides are synthesized).

Lesions processed by BER
Single bases in DNA can be chemically damaged by a variety of mechanisms, the most common ones being deamination, oxidation, and alkylation. These modifications can affect the ability of the base to hydrogen-bond, resulting in incorrect base-pairing, and, as a consequence, mutations in the DNA. For example, incorporation of adenine across from 8-oxoguanine (right) during DNA replication causes a G:C base pair to be mutated to T:A. Other examples of base lesions repaired by BER include:
 * Oxidized bases: 8-oxoguanine, 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG, FapyA)
 * Alkylated bases: 3-methyladenine, 7-methylguanosine
 * Deaminated bases: hypoxanthine formed from deamination of adenine. Xanthine formed from deamination of guanine. (Thymidine products following deamination of 5-methylcytosine are more difficult to recognize, but can be repaired by mismatch-specific glycosylases)
 * Uracil inappropriately incorporated in DNA or formed by deamination of cytosine

In addition to base lesions, the downstream steps of BER are also utilized to repair single-strand breaks.

The choice between long-patch and short-patch repair
The choice between short- and long-patch repair is currently under investigation. Various factors are thought to influence this decision, including the type of lesion, the cell cycle stage, and whether the cell is terminally differentiated or actively dividing. Some lesions, such as oxidized or reduced AP sites, are resistant to pol β lyase activity and, therefore, must be processed by long-patch BER.

Pathway preference may differ between organisms, as well. While human cells utilize both short- and long-patch BER, the yeast Saccharomyces cerevisiae was long thought to lack a short-patch pathway because it does not have homologs of several mammalian short-patch proteins, including pol β, DNA ligase III, XRCC1, and the kinase domain of PNKP. The recent discovery that the poly-A polymerase Trf4 possesses 5' dRP lyase activity has challenged this view.

DNA glycosylases
DNA glycosylases are responsible for initial recognition of the lesion. They flip the damaged base out of the double helix, as pictured, and cleave the N-glycosidic bond of the damaged base, leaving an AP site. There are two categories of glycosylases: monofunctional and bifunctional. Monofunctional glycosylases have only glycosylase activity, whereas bifunctional glycosylases also possess AP lyase activity. Therefore, bifunctional glycosylases can convert a base lesion into a single-strand break without the need for an AP endonuclease. β-Elimination of an AP site by a glycosylase-lyase yields a 3' α,β-unsaturated aldehyde adjacent to a 5' phosphate, which differs from the AP endonuclease cleavage product. Some glycosylase-lyases can further perform δ-elimination, which converts the 3' aldehyde to a 3' phosphate. A wide variety of glycosylases have evolved to recognize different damaged bases. Examples of DNA glycosylases include Ogg1, which recognizes 8-oxoguanine, MPG, which recognizes 3-methyladenine, and UNG, which removes uracil from DNA.

AP endonucleases
The AP endonucleases cleave an AP site to yield a 3' hydroxyl adjacent to a 5' deoxyribosephosphate (dRP). AP endonucleases are divided into two families based on their homology to the ancestral bacterial AP endonucleases endonuclease IV and exonuclease III. Many eukaryotes have members of both families, including the yeast Saccharomyces cerevisiae, in which Apn1 is the EndoIV homolog and Apn2 is related to ExoIII. In humans, two AP endonucleases, APE1 and APE2, have been identified. It is a member of the ExoIII family.

End processing enzymes
In order for ligation to occur, a DNA strand break must have a hydroxyl on its 3' end and a phosphate on its 5' end. In humans, polynucleotide kinase-phosphatase (PNKP) promotes formation of these ends during BER. This protein has a kinase domain, which phosphorylates 5' hydroxyl ends, and a phosphatase domain, which removes phosphates from 3' ends. Together, these activities ready single-strand breaks with damaged termini for ligation. The AP endonucleases also participate in 3' end processing. Besides opening AP sites, they possess 3' phosphodiesterase activity and can remove a variety of 3' lesions including phosphates, phosphoglycolates, and aldehydes. 3'-Processing must occur before DNA synthesis can initiate because DNA polymerases require a 3' hydroxyl to extend from.

DNA polymerases
Pol β is the main human polymerase that catalyzes short-patch BER, with pol λ able to compensate in its absence. These polymerases are members of the Pol X family and typically insert only a single nucleotide. In addition to polymerase activity, these enzymes have a lyase domain that removes the 5' dRP left behind by AP endonuclease cleavage. During long-patch BER, DNA synthesis is thought to be mediated by pol δ and pol ε along with the processivity factor PCNA, the same polymerases that carry out DNA replication. These polymerases perform displacing synthesis, meaning that the downstream 5' DNA end is "displaced" to form a flap (see diagram above). Pol β can also perform long-patch displacing synthesis and can, therefore, participate in either BER pathway. Long-patch synthesis typically inserts 2-10 new nucleotides.

Flap endonuclease
FEN1 removes the 5' flap generated during long patch BER. This endonuclease shows a strong preference for a long 5' flap adjacent to a 1-nt 3' flap. The yeast homolog of FEN1 is RAD27. In addition to its role in long-patch BER, FEN1 cleaves flaps with a similar structure during Okazaki fragment processing, an important step in lagging strand DNA replication.

DNA ligase
DNA ligase III along with its cofactor XRCC1 catalyzes the nick-sealing step in short-patch BER in humans. DNA ligase I ligates the break in long-patch BER.

Links with cancer
Defects in a variety of DNA repair pathways lead to cancer predisposition, and BER appears to follow this pattern. Deletion mutations in BER genes have shown to result in a higher mutation rate in a variety of organisms, implying that loss of BER could contribute to the development of cancer. Indeed, somatic mutations in Pol β have been found in 30% of human cancers, and some of these mutations lead to transformation when expressed in mouse cells. Mutations in the DNA glycosylase MYH are also known to increase susceptibility to colon cancer.

Epigenetic deficiencies in cancers
Epigenetic alterations (epimutations) in base excision repair genes have only recently begun to be evaluated in a few cancers, compared to the numerous previous studies of epimutations in genes acting in other DNA repair pathways (such as MLH1 in mismatch repair and MGMT in direct reversal). Some examples of epimutations in base excision repair genes that occur in cancers are summarized below.

MBD4
MBD4 (methyl-CpG-binding domain protein 4) is a glycosylase employed in an initial step of base excision repair. MBD4 protein binds preferentially to fully methylated CpG sites and to the altered DNA bases at those sites. These altered bases arise from the frequent hydrolysis of cytosine to uracil (see image) and hydrolysis of 5-methylcytosine to thymine, producing G:U and G:T base pairs. If the improper uracils or thymines in these base pairs are not removed before DNA replication, they will cause transition mutations. MBD4 specifically catalyzes the removal of T and U paired with guanine (G) within CpG sites. This is an important repair function since about 1/3 of all intragenic single base pair mutations in human cancers occur in CpG dinucleotides and are the result of G:C to A:T transitions. These transitions comprise the most frequent mutations in human cancer. For example, nearly 50% of somatic mutations of the tumor suppressor gene p53 in colorectal cancer are G:C to A:T transitions within CpG sites. Thus, a decrease in expression of MBD4 could cause an increase in carcinogenic mutations.

MBD4 expression is reduced in almost all colorectal neoplasms due to methylation of the promoter region of MBD4. Also MBD4 is deficient due to mutation in about 4% of colorectal cancers.

A majority of histologically normal fields surrounding neoplastic growths (adenomas and colon cancers) in the colon also show reduced MBD4 mRNA expression (a field defect) compared to histologically normal tissue from individuals who never had a colonic neoplasm. This finding suggests that epigenetic silencing of MBD4 is an early step in colorectal carcinogenesis.

In a Chinese population that was evaluated, the MBD4 Glu346Lys polymorphism was associated with about a 50% reduced risk of cervical cancer, suggesting that alterations in MBD4 may be important in cancer.

NEIL1
NEIL1 recognizes (targets) and removes certain oxidatively-damaged bases and then incises the abasic site via β,δ elimination, leaving 3′ and 5′ phosphate ends. NEIL1 recognizes oxidized pyrimidines, formamidopyrimidines, thymine residues oxidized at the methyl group, and both stereoisomers of thymine glycol. The best substrates for human NEIL1 appear to be the hydantoin lesions, guanidinohydantoin, and spiroiminodihydantoin that are further oxidation products of 8-oxoG. NEIL1 is also capable of removing lesions from single-stranded DNA as well as from bubble and forked DNA structures. A deficiency in NEIL1 causes increased mutagenesis at the site of an 8-oxo-Gua:C pair, with most mutations being G:C to T:A transversions.

A study in 2004 found that 46% of primary gastric cancers had reduced expression of NEIL1 mRNA, though the mechanism of reduction was not known. This study also found that 4% of gastric cancers had mutations in NEIL1. The authors suggested that low NEIL1 activity arising from reduced expression and/or mutation in NEIL1 was often involved in gastric carcinogenesis.

A screen of 145 DNA repair genes for aberrant promoter methylation was performed on head and neck squamous cell carcinoma (HNSCC) tissues from 20 patients and from head and neck mucosa samples from 5 non-cancer patients. This screen showed that NEIL1, with substantially increased hypermethylation, had the most significantly different frequency of methylation. Furthermore, the hypermethylation corresponded to a decrease in NEIL1 mRNA expression. Further work with 135 tumor and 38 normal tissues also showed that 71% of HNSCC tissue samples had elevated NEIL1 promoter methylation.

When 8 DNA repair genes were evaluated in non-small cell lung cancer (NSCLC) tumors, 42% were hypermethylated in the NEIL1 promoter region. This was the most frequent DNA repair abnormality found among the 8 DNA repair genes tested. NEIL1 was also one of six DNA repair genes found to be hypermethylated in their promoter regions in colorectal cancer.

Links with cognition

Active DNA methylation and demethylation is required for the cognition process of memory formation and maintenance. In rats, contextual fear conditioning can trigger life-long memory for the event with a single trial, and methylation changes appear to be correlated with triggering particularly long-lived memories. With contextual fear conditioning, after 24 hours, DNA isolated from the rat brain hippocampus region had 2097 differentially methylated genes, with a proportion being demethylated. As reviewed by Bayraktar and Kreutz, DNA demethylation is dependent on base excision repair (see figure).

Physical exercise has well established beneficial effects on learning and memory (see Neurobiological effects of physical exercise). BDNF is a particularly important regulator of learning and memory. As reviewed by Fernandes et al., in rats, exercise enhances the hippocampus expression of the gene Bdnf, which has an essential role in memory formation. Enhanced expression of Bdnf occurs through demethylation of its CpG island promoter at exon IV and demethylation depends on base excision repair (see figure).

Decline in BER with age
The activity of the DNA glycosylase that removes methylated bases in human leukocytes declines with age. The reduction in the excision of methylated bases from DNA suggests an age-dependent decline in 3-methyladenine DNA glycosylase, a BER enzyme responsible for removing alkylated bases.

Young rats (4- to 5 months old), but not old rats (24- to 28 months old), have the ability to induce DNA polymerase beta and AP endonuclease in response to oxidative damage.

title: Base excision repair