Zeynep ; Baharoglu

Keywords: SOS, stress, bacteria, adaptation, dna repair, antibiotic resistance

HAL is a

and DSBs are potent inducers of SOS as described in section I. B. Replication transcription collisions. Adapted from [START_REF] Helmrich | Transcription-replication encounters, consequences and genomic instability[END_REF]. Co-directional collisions may happen because of the difference of velocity of the replisome and the transcription complex, and lead to DSB formation [START_REF] Dutta | Linking RNA polymerase backtracking to genome instability in E. coli[END_REF]. Head-on collisions occur when transcription and replication progress in opposite directions. Both types of collisions cause DSB formation through either R-loop formation or topological stress, if rescue pathways are insufficient. C. Transcription stalling. Adapted from [START_REF] Wimberly | R-loops and nicks initiate DNA breakage and genome instability in non-growing Escherichia coli[END_REF]. Elongating RNA polymerase (RNAP) can stall upon encounter with a DNA lesion or bulky protein complexes. In this case, transcribed RNA can anneal to the template DNA forming a structure called R-loop. R-loops are another type of SOS inducers as described in section I. R-loops can lead to re-priming of a replication fork. If the re-primed replication fork encounters a nick, it can stall and lead to DSBs (as in panel A). 324x186mm (300 x 300 DPI)

Introduction

SOS induction was first observed in cells where the replication fork encounters DNA lesions which it tries to replicate [START_REF] Radman | SOS repair hypothesis: phenomenology of an inducible DNA repair which is accompanied by mutagenesis[END_REF]. Since these early investigations, a multitude of different studies have been carried out to decipher the triggers and components of the SOS response. We know now that other mechanisms, through which ssDNA is formed in the cell, exist and induce SOS.

The mechanism of induction of SOS by single stranded DNA (ssDNA) is well understood [START_REF] Walker | The SOS Response of Escherichia coli. Escherichia coli and Salmonella[END_REF][START_REF] Michel | After 30 years of study, the bacterial SOS response still surprises us[END_REF][START_REF] Kelley | Lex marks the spot: the virulent side of SOS and a closer look at the LexA regulon[END_REF] the SOS regulon by binding to its cognate LexA box sequence on their promoters. LexA proteolysis thus leads to de-repression of this regulon, comprised of about 40 genes in E. coli [START_REF] Courcelle | Comparative gene expression profiles following UV exposure in wild-type and SOS-deficient Escherichia coli[END_REF]. The affinity of LexA for these genes is variable and depends on the LexA box sequence itself and on the number of LexA boxes present at the promoters of these genes. The LexA box consensus sequence was proposed to be 5'-CTGTN 8 ACAG-3' [START_REF] Butala | The bacterial LexA transcriptional repressor[END_REF] and can be extended to 5′-TACTGT(AT) 4 ACAGTA-3′ in E. coli [START_REF] De Henestrosa | Identification of additional genes belonging to the LexA regulon in Escherichia coli[END_REF][START_REF] Wade | Genomic analysis of LexA binding reveals the permissive nature of the Escherichia coli genome and identifies unconventional target sites[END_REF]. LexA binding seems to be tolerant for variations in the sequence of 8 base spacer region but its length is invariant, as suggested by structural studies where the LexA-DNA complex was crystallized [START_REF] Zhang | Structure of the LexA-DNA complex and implications for SOS box measurement[END_REF]. This leads to differential de-repression [START_REF] Courcelle | Comparative gene expression profiles following UV exposure in wild-type and SOS-deficient Escherichia coli[END_REF])/re-repression of genes belonging to the SOS regulon as shown in vivo and in silico using an algorithm based approach by Ronen and colleagues [START_REF] Ronen | Assigning numbers to the arrows: parameterizing a gene regulation network by using accurate expression kinetics[END_REF]. On the other hand, the LexA box consensus sequence varies among bacterial species (cyanobacteria, gram positives, alphaproteobacteria, gammaproteobacteria). The phylogeny of LexA boxes and the ability of LexA proteins from various bacterial species to bind various LexA boxes was studied in vitro and in silico (Mazon et al., 2004) and shows that these sequences are related and in most cases follow the phylogenic relationships of those bacterial species. Examples of different LexA boxes are given in Table 1 -the list is non-exhaustive, but gives insight in the similarity of these sequences in different bacterial species.

The SOS-induced genes favor the repair of DNA lesions. Figure 1 shows simplified representations of DNA repair pathways induced by SOS.

Homologous recombination (HR): RecA itself is induced by SOS, together with other homologous recombination proteins such as RuvAB and RecFOR, to allow the repair of single stranded lesions. Induction of HR can lead to rearrangements in the chromosome (see section II-2-1).

Nucleotide Excision Repair (NER) by UvrABC (Sancar and Rupp, 1983): The uvr genes involved in nucleotide excision repair (NER) allow the repair of lesions where the DNA is double stranded (like a mismatch). Briefly, UvrABC endonuclease recognizes the lesion, nicks the DNA and UvrD helicase removes the DNA patch carrying the lesion [START_REF] Kumura | Stimulation of the UvrABC enzyme-catalyzed repair reactions by the UvrD protein (DNA helicase II)[END_REF]. DNA polymerase Pol I then fills the gap [START_REF] Husain | Repair of cis-platinum-DNA adducts by ABC excinuclease in vivo and in vitro[END_REF]. & Fuchs, 2003) and Pol IV (dinB) [START_REF] Napolitano | All three SOS-inducible DNA polymerases (Pol II, Pol IV and Pol V) are involved in induced mutagenesis[END_REF]. TLS can be highly mutagenic because translesion polymerases can incorporate a correct or incorrect base in front of the lesion on the template strand [START_REF] Friedberg | Specialized DNA polymerases, cellular survival, and the genesis of mutations[END_REF]. Unlike Pol III, TLS polymerases do not have a proofreading activity, except for Pol II that has a high level of fidelity on undamaged DNA. Induction of TLS leads to an increased frequency of spontaneous mutations (see section II-2).

LexA is a late-induced gene, and can stop the SOS induction when the genotoxic signal disappears and LexA cleavage is not favored anymore. Ongoing biochemical and sequence analysis studies aim at shedding light into the dynamics of SOS induction through the study of RecA-LexA interactions [START_REF] Kohiyama | Trashing of single-stranded DNA generated during processing of arrested replication fork in E. coli[END_REF] or biochemical and structural bases of auto-proteolysis and damage sensing [START_REF] Butala | The bacterial LexA transcriptional repressor[END_REF][START_REF] Aranda | Novel autoproteolytic and DNA-damage sensing components in the bacterial SOS response and oxidized methylcytosine-induced eukaryotic DNA demethylation systems[END_REF]. In an in vitro report about the timing of ssDNA-RecA-mediated self-cleavage of LexA, Butala and colleagues showed that a LexA repressor which is bound to its target lexA-box is insensitive to auto-proteolysis [START_REF] Butala | Interconversion between bound and free conformations of LexA orchestrates the bacterial SOS response[END_REF]. This observation explains how the binding affinity of LexA for different promoters correlates with the timing of the gene's expression.

SOS induction is a well-described cellular response. A comprehensive review about the mechanism of SOS induction and the phylogenetic conservation of this cellular stress response was published in 2007 by Erill, Campoy and Barbé [START_REF] Erill | Aeons of distress: an evolutionary perspective on the bacterial SOS response[END_REF]. In the light of subsequent studies, more knowledge has been accumulated on the conditions leading to the induction of the SOS response and its outcomes, such as virulence, persistence, emergence of multiple resistances and, more generally, adaptation. We focus in this review on new data uncovering the SOS-related strategies developed by bacteria in response to various aggressions.

-Origin of ssDNA in the absence of external damaging agents

Most ssDNA originates from double strand breaks (DSBs). As described in the introduction, ssDNA is the sole inducer of the SOS response. Experiments measuring the formation of DNA lesions capable of inducing SOS in E. coli using flow cytometry led to the observation that most of the chromosomal ssDNA (two thirds according to the authors) comes from the action of RecBCD on DSBs. The remaining third are ssDNA stretches formed independently of RecBCD [START_REF] Pennington | Spontaneous DNA breakage in single living Escherichia coli cells[END_REF]. Such DSBs mostly originate from spontaneous DNA breakage during replication, most probably after fork stalling (Figure 2A). Several conditions leading to replication arrest are described below.

Replication fork problems can lead to DSB formation. It is known that replication arrest or stalling leads to formation of ssDNA on the lagging strand template, which constitutes a substrate for the formation of the RecA nucleofilament and SOS induction in the absence of DNA lesions [START_REF] Walker | The SOS Response of Escherichia coli. Escherichia coli and Salmonella[END_REF]. Such an event can happen when replication is impaired, as is the case for E. coli conditional replication mutants harboring thermo-sensitive alleles of genes coding for different sub-units of the replicative DNA polymerase Pol III [START_REF] Flores | A fork-clearing role for UvrD[END_REF][START_REF] Lestini | UvrD controls the access of recombination proteins to blocked replication forks[END_REF]. Figure 2A shows a synthetic representation of how ssDNA that induces SOS can be formed during replication. Replication arrests may also occur upon transcription replication collisions (Figure 2B), such as in conditions where bulky factors block the DNA polymerase complex. Such an example is described in an E. coli strain where the highly transcribed ribosomal rrn operons were inverted in order to be transcribed in the opposite direction of replication [START_REF] Boubakri | The helicases DinG, Rep and UvrD cooperate to promote replication across transcription units in vivo[END_REF]. In this case, head-on collisions of the replisome with the bulky transcription complexes hinder the progression of the replication fork and lead to SOS induction. In the absence of stalled RNA polymerase (RNAP) removal systems, the DNA replication is impaired and SOS is induced [START_REF] Boubakri | The helicases DinG, Rep and UvrD cooperate to promote replication across transcription units in vivo[END_REF][START_REF] Mcglynn | The conflict between DNA replication and transcription[END_REF].

R-loop formation in non-replicating bacteria also leads to DSB formation (Figure 2C).

The conditions described above involve replication fork stalling, which implies active replication of the bacterial chromosome. However, DSBs are also formed in non-replicating conditions. The origin of these DSBs was found to lie in R-loop formation during transcription in E. coli [START_REF] Wimberly | R-loops and nicks initiate DNA breakage and genome instability in non-growing Escherichia coli[END_REF]. R-loops are RNA-DNA hybrids that are formed when the RNAP is stalled on DNA and the RNA in synthesis anneals to the . coli (reviewed in (McGlynn et al., 2012)) and eukaryotes [START_REF] Helmrich | Collisions between replication and transcription complexes cause common fragile site instability at the longest human genes[END_REF]. This can happen, for example, when the RNA polymerase encounters a roadblock and backtracks [START_REF] Dutta | Linking RNA polymerase backtracking to genome instability in E. coli[END_REF]. In growing cells, this can lead to replication-transcription conflicts as described above (for a review, see [START_REF] Merrikh | Replication-transcription conflicts in bacteria[END_REF]). R-loops were shown to lead to genomic instability in E. coli, as in eukaryotes [START_REF] Gan | R-loop-mediated genomic instability is caused by impairment of replication fork progression[END_REF], by impairing DNA replication.

Formation of such R-loop structures was very recently shown to also lead to stressinduced mutations in non-replicating E. coli [START_REF] Wimberly | R-loops and nicks initiate DNA breakage and genome instability in non-growing Escherichia coli[END_REF], suggesting that problems at transcribed regions leading to RNAP stalling can constitute a genotoxic signal.

-ssDNA formation due to external damaging agents

DNA damage can be formed upon physical insults and ssDNA can also originate from DNA damage provoked by external agents. For instance, UV irradiation causes DNA lesions that need to be repaired in order for the cell to survive. The repair of damaged DNA by HR or TLS requires the initial recruitment of RecA to the site of lesion [START_REF] Fujii | RecFOR proteins are essential for Pol V-mediated translesion synthesis and mutagenesis[END_REF]. Hence, inactivating the recruitment of RecA, for instance in a mutant deleted for recA, leads to cell death because of lack of repair and possibly because of inefficient TLS in the absence of SOS induction. As mentioned in the introduction, SOS induction leads to the expression of TLS polymerases; hence, the repair of UV lesions is highly mutagenic.

Another damaging factor described by Aertsen and colleagues is pressure. High pressure indeed induces SOS through DSB formation through the Mrr nuclease [START_REF] Aertsen | Mrr instigates the SOS response after high pressure stress in Escherichia coli[END_REF], in E. coli strains carrying the mrr gene [START_REF] Aertsen | Activation of the Salmonella typhimurium Mrr protein[END_REF]. In turn, SOS can induce high pressure resistance through spontaneous mutations inactivating the mrr gene [START_REF] Aertsen | Mrr instigates the SOS response after high pressure stress in Escherichia coli[END_REF]. What is remarkable in this example is how the induction of the SOS response is a subtle way for the cell to turn an external aggression into an advantage by becoming better adapted to its environment.

Another study on the effect of gamma radiation on E. coli reports a link between the SOS response and radiation-induced cell death, a bacterial mechanism similar to the eukaryotic programmed cell death [START_REF] Wadhawan | A component of gamma-radiation-induced cell death in E. coli is programmed and interlinked with activation of caspase-3 and SOS response[END_REF]. Moreover, SOS-dependent DNA repair by HR and TLS were found to be necessary for cell recovery after gamma irradiation.

Reactive oxygen species (ROS) can also lead to DSB formation. Recently, reactive oxygen species and their various effects on cellular mechanisms have drawn a lot of attention.

ROS-like superoxide or hydroxyl radicals (OH -) are potent bacterial stressors, which can For instance, superoxide leads to the release of free iron ions from proteins containing iron (Fe-S cluster proteins) [START_REF] Keyer | Superoxide accelerates DNA damage by elevating free-iron levels[END_REF][START_REF] Imlay | Pathways of oxidative damage[END_REF]. Iron can also localize along the phosphodiester backbone of nucleic acids. Moreover, high concentrations of free ferrous iron lead to the production of hydroxyl radicals (OH -) through the Fenton reaction [START_REF] Henle | Sequence-specific DNA cleavage by Fe2+-mediated fenton reactions has possible biological implications[END_REF][START_REF] Rai | Localization of Fe(2+) at an RTGR sequence within a DNA duplex explains preferential cleavage by Fe(2+) and H2O2[END_REF] [START_REF] Daly | A new perspective on radiation resistance based on Deinococcus radiodurans[END_REF]. OH -attacks the DNA backbone and ultimately causes DSBs [START_REF] Jena | DNA damage by reactive species: Mechanisms, mutation and repair[END_REF]. Moreover, superoxide and OH -are also formed after poisoning of the DNA gyrase (by fluoroquinolones or proteic inhibitors like the CcdB toxin), an essential protein for chromosome replication [START_REF] Dwyer | Gyrase inhibitors induce an oxidative damage cellular death pathway in Escherichia coli[END_REF].

Another type of DNA damage caused by oxidative attack is the incorporation of oxidized guanine residues during replication (7,8-Dihydro-8-oxo-guanine or 8-oxo-G) [START_REF] Sussenbach | Photodynamic degradation of guanine[END_REF]. Bacteria possess a defense system against such damage, first by hydrolyzing the oxidized guanine present in the nucleotide pool and second, by affecting the incorporated G through the base excision repair pathway (BER) [START_REF] Lu | Repair of oxidative DNA damage: mechanisms and functions[END_REF], by limiting its incorporation and the formation of mismatches [START_REF] Sobol | For MutY, it's all about the OG[END_REF]. Incomplete action of the BER system possibly leads to DSBs that are cytotoxic if unrepaired [START_REF] Foti | Oxidation of the guanine nucleotide pool underlies cell death by bactericidal antibiotics[END_REF].

ROS can also indirectly cause DNA damage [START_REF] Farr | Oxidative Stress Responses in Escherichia-Coli and Salmonella-Typhimurium[END_REF]. OH -radicals can damage proteins [START_REF] Ide | Thymine glycols and urea residues in M13 DNA constitute replicative blocks in vitro[END_REF] and lipids [START_REF] Schaich | Fenton reactions in lipid phases[END_REF] as shown in E. coli and Salmonella enterica [START_REF] Paez | Comparison of macromolecular oxidation by reactive oxygen species in three bacterial genera exposed to different antibiotics[END_REF] (also reviewed in [START_REF] Dwyer | Role of reactive oxygen species in antibiotic action and resistance[END_REF]). Additionally, it is known that mistranslated and misfolded proteins are more susceptible to oxidation [START_REF] Dukan | Protein oxidation in response to increased transcriptional or translational errors[END_REF]. Mistranslational corruption of proteins may lead to replication fork collapse and induction of the SOS response in E. coli [START_REF] Balashov | Mistranslation induced by streptomycin provokes a RecABC/RuvABC-dependent mutator phenotype in Escherichia coli cells[END_REF][START_REF] Mamun | Hypermutagenesis in mutA cells is mediated by mistranslational corruption of polymerase, and is accompanied by replication fork collapse[END_REF]. Interestingly, in Deinococcus radiodurans, cell death by radiation is not caused by direct DNA damage but primarily by oxidative damage of proteins, which eventually results in the abolition of DNA repair [START_REF] Krisko | Protein damage and death by radiation in Escherichia coli and Deinococcus radiodurans[END_REF]. The legendary resistance of D. radiodurans to ionizing radiations is actually a consequence of a more efficient proteome protection against ROS rather than a more efficient genome protection and cell death correlates with protein carbonylation due to oxidative damage. Preserving cell integrity in times of oxidation seems to depend as much on proteome protection against ROS then on DNA protection. Furthermore, affecting the integrity of the proteome can result in the induction of the SOS response through impaired DNA replication and repair.

Antibiotics can trigger bacterial stress at both lethal and sub-lethal concentrations. gyrase [START_REF] Pohlhaus | Norfloxacin-induced DNA gyrase cleavage complexes block Escherichia coli replication forks, causing double-stranded breaks in vivo[END_REF], and trimethoprim [START_REF] Lewin | The role of the SOS response in bacteria exposed to zidovudine or trimethoprim[END_REF] which affects purine and pyrimidine synthesis, do not directly generate lesions but rather perturb DNA replication. Mitomycin C (MMC) leads to T-T crosslinks that lead to DNA break formation. β -lactams were also reported to induce SOS in some conditions by an unusual mechanism. In E. coli, β-lactams cause cell wall damage, which induces the two-component system proteins DpiBA. DpiA can bind the origin of replication of the chromosome and, together with DpiB, impair replication, which results in the induction of the SOS response [START_REF] Miller | DpiA binding to the replication origin of Escherichia coli plasmids and chromosomes destabilizes plasmid inheritance and induces the bacterial SOS response[END_REF][START_REF] Miller | SOS response induction by beta-lactams and bacterial defense against antibiotic lethality[END_REF].

Antibiotics may induce SOS

Interestingly, SOS is also induced by low doses of several antibiotics, termed sub-MIC for sub-minimal inhibitory concentration. The evidence that sub-MICs of antibiotics play an important role in the appearance and dissemination of antibiotic resistance has emerged in recent years (Kohanski et al., 2010[START_REF] Gullberg | Selection of resistant bacteria at very low antibiotic concentrations[END_REF]. This is especially relevant considering that a large proportion of ingested antibiotics are released intact in the environment (Liu et al., 1999, Liu et al., 1999) and that low levels of antibiotics are found in wastewater plants, hospitals and soil [START_REF] Fick | Contamination of surface, ground, and drinking water from pharmaceutical production[END_REF][START_REF] Haggard | Net changes in antibiotic concentrations downstream from an effluent discharge[END_REF], Kummerer, 2009, Kummerer, 2009).

First, sub-MICs FQs have been shown to induce SOS in Salmonella enterica, even if bacterial growth is not affected by these low concentrations [START_REF] Yim | Modulation of Salmonella gene expression by subinhibitory concentrations of quinolones[END_REF]. Ciprofloxacin at sub-MIC induces SOS and increases the frequency of point mutations in S. aureus [START_REF] Mesak | Effects of subinhibitory concentrations of antibiotics on SOS and DNA repair gene expression in Staphylococcus aureus[END_REF][START_REF] Mesak | Phenotypic changes in ciprofloxacin-resistant Staphylococcus aureus[END_REF]. Moreover, ampicillin at sub-MIC was found to downregulate mismatch repair in E. coli, P. aeruginosa and V. cholerae, hence increasing mutation frequencies due to SOS [START_REF] Gutierrez | beta-lactam antibiotics promote bacterial mutagenesis via an RpoS-mediated reduction in replication fidelity[END_REF]. This brings along a different problem than SOS induction by the same antibiotics at high concentrations: in fact, at high concentration, bacteria either acquire mutations that help them to survive or they die, the latter possibility being the most likely. However, at low antibiotic concentrations, bacteria do not die and SOS induction leads to an increase in bacterial genome variability. Mutations acquired in such a way can then be fixed in populations if they provide a fitness advantage. More and more reports now suggest that these low concentrations of antibiotics and the consequent induction 8 to induce SOS. Interestingly V. cholerae, but not E. coli, was found to induce SOS in response to these antibiotics, which favors the appearance of resistant derivatives (Baharoglu et al., 2010). Moreover, aminoglycoside (AG) mediated SOS induction is conserved among distantly related Gram negative pathogens (Klebsiella pneumoniae and Photorhabdus luminescens), suggesting that E coli is more of an exception than a paradigm for the physiological response to sub-MICs of antibiotics (Baharoglu et al., 2013). It is also interesting to mention here that AGs block translation. In fact, translating ribosomes control the transcription elongation rate: active ribosomes can prevent RNAP from backtracking [START_REF] Proshkin | Cooperation between translating ribosomes and RNA polymerase in transcription elongation[END_REF][START_REF] Potenski | R we there yet? R-loop hazards to finishing the journey[END_REF]. Consequently, inhibiting protein synthesis increases levels of transcription-generated R-loops. Formation of transcriptional R-loops in bacteria is indeed shown to be inhibited by ribosomes on the nascent transcript [START_REF] Masse | Escherichia coli DNA topoisomerase I inhibits R-loop formation by relaxing transcription-induced negative supercoiling[END_REF]. As described in section I-1, R-loops have the potential to induce SOS.

Aminoglycosides target protein translation, but they clearly also have a negative effect on transcription and replication at sub-MIC, which leads to SOS induction in several bacterial species.

It can sound puzzling that sub-MICs of AGs induce SOS in several bacteria for they do not directly target DNA synthesis or the DNA molecule. These observations point to a role for intermediate factors that cause DNA damage. One of the reasons for this SOS induction was actually found to be that sub-MIC AG treatment leads to the formation of ROS (Baharoglu et al., 2013). Further studies suggest a role for RNA polymerase stalling at AGmediated DNA lesions and formation of R-loops with the consequences on SOS as described in the previous paragraph (Baharoglu et al., 2013).

Several points are striking in these latter findings. First, low concentrations of antibiotics that do not affect cell growth -even those that do not target DNA or its replication -have the power of inducing the bacterial SOS response and as such increasing mutation frequencies of bacteria [START_REF] Baharoglu | Vibrio cholerae triggers SOS and mutagenesis in response to a wide range of antibiotics: a route towards multiresistance[END_REF]. Second, formation of ROS is the factor leading to the actual DNA damage, as discussed above. Finally, and once again, a tight connection between transcription blocks and triggering of the SOS response is seen. Induction of SOS by low levels of AGs is important for growth under these conditions. This aspect of SOS induction needs further work in order to be fully understood.

-ssDNA formation during ssDNA uptake

Transformation is a mechanism of HGT that relies on ssDNA uptake and processing [START_REF] Dubnau | DNA uptake in bacteria[END_REF]. Transformation occurs when a bacterial cell reaches a competent state rendering it capable of taking up DNA present in its environment and, in some cases, of integrating the acquired DNA in its genome by recombination [START_REF] Claverys | The genetic transformation machinery: composition, localization, and mechanism[END_REF]. It was observed long ago in Bacillus subtilis that when lysogenic strains were rendered competent, the induction of a prophage led to the reduction in the frequency of transformation [START_REF] Yasbin | Transformation and transfection in lysogenic strains of Bacillus subtilis: evidence for selective induction of prophage in competent cells[END_REF][START_REF] Mcveigh | Phenotypic differentiation of "smart" versus "naive" bacteriophages of Bacillus subtilis[END_REF]. This was not due to reduced transformation efficiency but rather to the induction of a prophage in the recipient cells leading to the lysis of the cell and thus a drop in the number of viable transformants. Prophage induction is in many cases SOS-dependent. It is likely that the reduced transformation efficiency of lysogenic cells compared to non-lysogenic cells is the result of induction of the SOS response by the ssDNA acquired during transformation. Furthermore, it was shown in naturally competent V. cholerae that ssDNA uptake during competence induces the SOS response [START_REF] Baharoglu | Transformation-induced SOS regulation and carbon catabolite control of the V. cholerae integron integrase: connecting environment and genome plasticity[END_REF].

In addition to transformation, conjugation is another HGT mechanism where plasmid or chromosomal DNA from a donor strain enters the recipient cell in a single stranded fashion. Like transformation, conjugation also induces SOS in E. coli and V. cholerae (Baharoglu et al., 2010).

II -Consequences of SOS induction.

-Repair

As mentioned earlier, the SOS response triggers homologous recombination, required especially for the repair of double strand ends/breaks (DSB/DSE). A recent study in E. coli

proposed that instead of a genome wide search for homology, genotoxic stress-induced and RecA-dependent condensation of sister chromosomes, which are otherwise segregated at cell poles, allow repair of DSBs [START_REF] Shechter | Stress-induced Condensation of Bacterial Genomes Results in Re-Pairing of Sister Chromosomes: Implications for Double-Strand DNA Break Repair[END_REF]. Such genome packaging is also observed in E. coli in response to oxidative stress [START_REF] Ko | Mechanisms of action of escapin, a bactericidal agent in the ink secretion of the sea hare Aplysia californica: rapid and long-lasting DNA condensation and involvement of the OxyR-regulated oxidative stress pathway[END_REF]. Moreover, the importance of RecN was recently discovered for the repair of DSBs after treatment with MMC, a DNA-damaging agent that leads to DSB formation [START_REF] Keyamura | RecA recruits SMC-like RecN to DNA double-strand breaks[END_REF] Moreover, the importance of SOS induction in the case of replication-transcription conflicts described above is notable. Indeed, in E. coli strains in which the transcription of rrn operons leads to replication arrest after stalling of the RNAP, preventing induction of the SOS response results in a decrease in fitness (or even absence of growth) [START_REF] Boubakri | The helicases DinG, Rep and UvrD cooperate to promote replication across transcription units in vivo[END_REF].

RNAP stalling can be an obstacle to the progression of the replication fork and needs to be dislodged [START_REF] Mcglynn | The conflict between DNA replication and transcription[END_REF]. Intermediate DNA structures, R-loops, capable of inducing SOS are formed at the stalled RNA polymerase. By inducing expression of genes coding for helicases such as DinG, SOS also allows the processing and removal of bulky protein complexes that prevent DNA polymerase action (Baharoglu et al., 2010). Additionally, DinG was proposed to inhibit the formation and accumulation of R-loops in vivo in E. coli cells [START_REF] Boubakri | The helicases DinG, Rep and UvrD cooperate to promote replication across transcription units in vivo[END_REF][START_REF] De Septenville | Replication fork reversal after replication-transcription collision[END_REF].

Recent data also shows that transcription stalling is involved in SOS induction in response to DNA damage by sub-MIC AGs in V. cholerae (Baharoglu et al., 2013), with a role for the RNAP-binding protein Mfd. In fact, the helicase Mfd can recognizes R-loops at sites where the RNAP is stalled on damaged DNA and releases the transcription complex [START_REF] Roberts | Mfd, the bacterial transcription repair coupling factor: translocation, repair and termination[END_REF][START_REF] Deaconescu | Structural basis for bacterial transcription-coupled DNA repair[END_REF][START_REF] Savery | The molecular mechanism of transcription-coupled DNA repair[END_REF]. Interestingly, Mfd is also required for the repair of DSBs caused by MMC in Helicobacter pylori, where an mfd mutant is susceptible to antibiotics and has a DNA repair defect [START_REF] Lee | The Helicobacter pylori Mfd protein is important for antibiotic resistance and DNA repair[END_REF]. Mfd is involved in increased mutation frequencies after FQ treatment in Campylobacter jejuni as well [START_REF] Han | Key role of Mfd in the development of fluoroquinolone resistance in Campylobacter jejuni[END_REF]. All of these observations point to Mfd as a possible partner of the SOS response.

There is also evidence that the NusA protein, a component of the elongating RNA polymerase, is involved in stress-induced mutagenesis by interacting with the TLS polymerase Pol IV in E. coli [START_REF] Cohen | The transcription elongation factor NusA is required for stress-induced mutagenesis in Escherichia coli[END_REF]. This is once again evidence highlighting an undeniable connection between transcription and induction of the SOS response.

-Change: outcome of SOS induction in terms of genome plasticity and gene expression

As described in the introduction, SOS induction increases the levels of proteins 11 SOS (after treatment with sub-MIC of FQ) [START_REF] Lopez | Effect of subinhibitory concentrations of antibiotics on intrachromosomal homologous recombination in Escherichia coli[END_REF]. Interestingly, it was found in V. cholerae that homologous recombination plays an unsuspected role in chromosome fusions. V. cholerae has two circular chromosomes with different origins of replication. Under genetic conditions leading simultaneously to impaired replication from the origin of the second chromosome and to induction of the SOS response, it was found that homologous recombination proceeds to the fusion of the two chromosomes through homologous IS sequences present in both chromosomes, giving rise to changes in gene dosage [START_REF] Val | Fuse or die: how to survive the loss of Dam in Vibrio cholerae[END_REF]. In fact, the closer a gene is to the origin of replication, the more its copy number in a given cell increases due to multiple firings of replication. When two chromosomes are fused, only one origin is active, thus the gene dosage is subject to change.

This suggests that in the wild type strain, such fusions can happen even if they are not easily detected and that SOS induction can favor their occurrence, which can influence gene expression and cell physiology in general.

Interestingly, DSB formation and subsequent SOS induction can also constitute an advantage in harsh conditions: it was shown in pathogenic Pseudomonas aeruginosa biofilm communities that ROS-mediated formation of DSBs were beneficial to bacteria in the presence of antibiotics as they allowed genome rearrangements and resistance [START_REF] Boles | Endogenous oxidative stress produces diversity and adaptability in biofilm communities[END_REF].

In addition to HR, SOS leads to increased mutation frequencies through TLS.

Induction of SOS leads to a high state of mutability in the bacterial cells, for example after antibiotic treatment in E. coli [START_REF] Ysern | Induction of SOS genes in Escherichia coli and mutagenesis in Salmonella typhimurium by fluoroquinolones[END_REF]. This allows them to increase their chances of generating mutations that will permit them to survive under the stress conditions they are submitted to. Indeed, point mutations can result in antibiotic resistance acquisition. For instance, resistance to ciprofloxacin (FQ) and to rifampicin is due to mutations caused during the induction of the SOS response through the action of the error-prone polymerases IV/V [START_REF] Cirz | Induction and inhibition of ciprofloxacin resistanceconferring mutations in hypermutator bacteria[END_REF]. Sub-MICs of FQs were clearly shown to cause the development of resistance in S. aureus [START_REF] Didier | Impact of ciprofloxacin exposure on Staphylococcus aureus genomic alterations linked with emergence of rifampin resistance[END_REF] and S. enterica [START_REF] Hughes | Selection of resistance at lethal and non-lethal antibiotic concentrations[END_REF].

The increased mutation frequency in the presence of FQs was proposed to lead to the overload of MutS-dependent mismatch repair, causing the accumulation of unrepaired DNA and the appearance of point mutations that lead to antibiotic resistance. , 2008). The authors conclude that there is a close correlation between UmuD' 2 C levels and mutation frequency (for a review on UV-mediated DNA damage and repair, see [START_REF] Rastogi | Molecular mechanisms of ultraviolet radiation-induced DNA damage and repair[END_REF]). (DSB)-dependent stress-induced mutagenesis described in starving E. coli also requires the SOS response and DinB (Pol IV) [START_REF] Shee | What limits the efficiency of doublestrand break-dependent stress-induced mutation in Escherichia coli?[END_REF]. Interestingly, even in mismatch repair deficient hyper-mutator strains, inactivation of the SOS response leads to reduced development of antibiotic resistant bacteria [START_REF] Cirz | Induction and inhibition of ciprofloxacin resistanceconferring mutations in hypermutator bacteria[END_REF], showing the importance of SOS induction in the appearance of point mutations.

It was found that SOS induction mediated by sub-MIC antibiotics is also coupled with an increased frequencies of spontaneous mutation in E. coli and V. cholerae (the appearance of rifampicin resistance increased from 10 -9 to around 10 -8 ) [START_REF] Baharoglu | Vibrio cholerae triggers SOS and mutagenesis in response to a wide range of antibiotics: a route towards multiresistance[END_REF].

Such a modest increase in mutation frequency is nonetheless of high importance since it was shown to influence the evolution of multidrug resistance in E. coli [START_REF] Denamur | Intermediate mutation frequencies favor evolution of multidrug resistance in Escherichia coli[END_REF].

Strains characterized by low or high mutation rates actually have a lower resistance to antibiotics than strains that have an intermediate rate of mutation (around 10 -8 ), regardless of the antibiotic tested [START_REF] Denamur | Intermediate mutation frequencies favor evolution of multidrug resistance in Escherichia coli[END_REF]. In fact, high mutation frequencies probably more often lead to deleterious mutations, demonstrating that SOS induction levels can be subtly fine-tuned in order to achieve adapted levels of mutability.

SOS induction in response to HGT also leads to genome rearrangements. As mentioned in section I-3, during conjugation and transformation, plasmid or chromosomal DNA enters the recipient cell in a single stranded fashion. The fact that HGT (i.e. incoming DNA) induces SOS in the recipient is not trivial: by doing so, incoming DNA may induce its own integration in the recipient bacterium's genome, highlighting once more the role of the SOS response as an initiator of genome plasticity and in the acquisition of adaptation factors.

Interestingly, even narrow host range conjugative plasmids which cannot replicate or be maintained in the recipient bacteria induce SOS upon entry into the cell (Baharoglu et al., 2010). This means that even though the incoming plasmid is not maintained and the incoming DNA is eventually degraded, conjugation still leaves an imprint in the recipient by inducing SOS-dependent genome plasticity such as point mutations or integron rearrangement, as discussed in the following paragraph.

As depicted above, SOS is a stress response inducing the expression of recombination and repair genes. But other genes are also part of the SOS regulon and induced following genotoxic stress. For example, apart from inducing mutation frequency, another way for the SOS response to confer antibiotic resistance and adaptive responses is through increasing the quinolones is here triggered by the presence of quinolones themselves, at sub-inhibitory concentrations, or by other antibiotics that induce the SOS response. This latter point is important. It means that bacteria not only become resistant to the factor triggering the genotoxic stress, but also modulate their gene expression and modify their genome (spontaneous mutations, genome rearrangements) so that they become able to resist to other stresses when they come along. In this way, SOS is a powerful strategy of bacteria to turn external aggressions in their favor. SOS is also involved in other bacterial processes such as persistence, virulence and biofilm formation.

Persistence is a non-hereditary and reversible state. Persisters are antibiotic tolerant cells that are not killed during treatment and resume growth when antibiotics are removed (for a review [START_REF] Lewis | Persister Cells[END_REF]). Dorr et al. showed that E. coli persisters are not pre-existing dormant cells but that their formation is rather induced by the SOS response after FQ treatment [START_REF] Dorr | SOS response induces persistence to fluoroquinolones in Escherichia coli[END_REF]. Interestingly, the appearance of persister cells was shown to be much higher during treatment with a sub-MIC of FQ than when higher antibiotic concentrations were used (stronger SOS induction). SOS induction was thus necessary, but a low level of induction was found to be more favorable to the development of persistence. Interestingly, in a report about the dynamics of SOS induction, Butala and colleagues observed that the dissociation rate of

LexA from the promoters it regulates -which correlates with the levels of SOS inductiondirectly influences the formation of E. coli persisters [START_REF] Butala | Interconversion between bound and free conformations of LexA orchestrates the bacterial SOS response[END_REF].

SOS-induced dormancy was shown to be due to TisB toxin induction by SOS [START_REF] Dorr | Ciprofloxacin causes persister formation by inducing the TisB toxin in Escherichia coli[END_REF]. Indeed, persister cell formation can occur through the induction of toxins from the toxin-antitoxin family, such as TisB from the SOS regulon, which decreases the growth rate (drop of ATP levels, no active peptidoglycan synthesis, no ribosome formation, no replication), causing tolerance to multiple antibiotics. Interestingly, toxin-antitoxin modules are found in many bacterial genomes [START_REF] Pandey | Toxin-antitoxin loci are highly abundant in free-living but lost from host-associated prokaryotes[END_REF][START_REF] Leplae | Diversity of bacterial type II toxin-antitoxin systems: a comprehensive search and functional analysis of novel families[END_REF], and TisB may not be the only toxin that leads to persistence. Therefore, the use of SOS-inducing antibiotics at sub-MICs may lead to persistence and eventually contribute to the development of multidrug resistance. In fact, other examples of SOS-related TA modules exist, like the E.

coli YafNO system which is induced by SOS [START_REF] Singletary | An SOS-regulated type 2 toxin-antitoxin system[END_REF] [START_REF] Karoui | Ham22, a mini-F mutation which is lethal to host cell and promotes recA-dependent induction of lambdoid prophage[END_REF][START_REF] Bernard | Cell killing by the F plasmid CcdB protein involves poisoning of DNA-topoisomerase II complexes[END_REF].

In addition to resistance to stress and adaptation, SOS induction also triggers virulence in some bacteria. Indeed, SOS can directly regulate virulence factors: for example, LexA regulates the expression of the V. cholerae prophage CTX genes leading to production of the cholerae toxin [START_REF] Kimsey | Vibrio cholerae LexA coordinates CTX prophage gene expression[END_REF]) [START_REF] Quinones | LexA cleavage is required for CTX prophage induction[END_REF]. SOS induced in response to sub-MIC of antibiotics also triggers the production of the shiga-toxin (Stx) in pathogenic E.

coli [START_REF] Nassar | Effects of Subinhibitory Concentrations of Antimicrobial Agents on Escherichia coli O157:H7 Shiga Toxin Release and Role of the SOS Response. Foodborne pathogens and disease[END_REF]. Furthermore, SOS induces horizontal dissemination of virulence factors present in pathogenicity islands in S. aureus [START_REF] Ubeda | Antibiotic-induced SOS response promotes horizontal dissemination of pathogenicity island-encoded virulence factors in staphylococci[END_REF], which can happen for instance in response to antibiotic treatment [START_REF] Maiques | beta-lactam antibiotics induce the SOS response and horizontal transfer of virulence factors in Staphylococcus aureus[END_REF].

Biofilm formation and quorum sensing can also be linked to the SOS response and DNA damage in some cases. For instance, in V. harveyi, induction of bioluminescence was shown to be important for repair of DNA damage caused by UV irradiation [START_REF] Czyz | Vibrio harveyi bioluminescence plays a role in stimulation of DNA repair[END_REF]. Bioluminescence is regulated by quorum sensing and Czyz et al found that UV irradiation induces bioluminescence. In subsequent studies, the authors showed that while bioluminescence has a fitness cost on growing V. harveyi it confers a selective advantage under conditions of DNA damage (caused by low doses of UV irradiation) [START_REF] Czyz | Stimulation of DNA repair as an evolutionary drive for bacterial luminescence[END_REF]. Although these studies do not directly demonstrate a link between the SOS response and quorum sensing in the repair of damaged DNA, together with data suggesting that quorum sensing is involved in SOS induction by sub-MIC of antibiotics [START_REF] Baharoglu | Vibrio cholerae triggers SOS and mutagenesis in response to a wide range of antibiotics: a route towards multiresistance[END_REF], such a link seems plausible. Quorum sensing also regulates biofilm formation in V.

cholerae [START_REF] Hammer | Quorum sensing controls biofilm formation in Vibrio cholerae[END_REF][START_REF] Zhu | Quorum sensing-dependent biofilms enhance colonization in Vibrio cholerae[END_REF]. On the basis that replicationinhibiting antibiotics induce biofilm formation in various bacterial species [START_REF] Hoffman | Aminoglycoside antibiotics induce bacterial biofilm formation[END_REF][START_REF] Kaplan | Antibiotic-induced biofilm formation[END_REF], Gotoh and colleagues tested and found that the SOS response is involved in biofilm formation by P. aeruginosa [START_REF] Gotoh | SOS involvement in stressinducible biofilm formation[END_REF]. Moreover, taking into account reports showing that natural conjugation in E. coli [START_REF] Ghigo | Natural conjugative plasmids induce bacterial biofilm development[END_REF] and extracellular DNA uptake in Staphylococcus epidermidis, which induce SOS, also induce biofilm formation [START_REF] Kaplan | Extracellular DNA-dependent biofilm formation by Staphylococcus epidermidis RP62A in response to subminimal inhibitory concentrations of antibiotics[END_REF], and that the pathways regulating biofilm formation and quorum sensing are intertwined, it is appealing to address in the future the possible links between quorum sensing, biofilm formation and the SOS response. and integron recombination leading to β-lactam and ceftazidime resistance [START_REF] Hocquet | Evidence for induction of integron-based antibiotic resistance by the SOS response in a clinical setting[END_REF]. Moreover, in their recent study, they report the action of metronidazole on antibiotic resistance acquisition in P. aeruginosa. They show that metronidazole, which is used against anaerobic bacteria and not against P. aeruginosa triggers nevertheless the SOS stress response in this bacterium. In turn SOS can trigger the appearance of resistances to multiple antibiotics in P. aeruginosa. The authors clearly show the induction of SOS by metronidazole and correlate this with increased resistance to aminoglycosides and fluoroquinolones in vitro [START_REF] Hocquet | Metronidazole increases the emergence of ciprofloxacin-and amikacin-resistant Pseudomonas aeruginosa by inducing the SOS response[END_REF]).

An integron is a genetic platform of promoterless open reading frames called gene cassettes, separated by recombination sites. The integron integrase, which encodes a sitespecific recombinase, catalyzes excision and integration of these cassettes in a single stranded circular form (for a review, see [START_REF] Mazel | Integrons: agents of bacterial evolution[END_REF]. Other than integron rearrangements, the integrase also allows the capture of exogenous circular promoterless gene cassettes. Gene cassettes placed at the first positions of the integron can be expressed from a constitutive promoter [START_REF] Levesque | Diversity and relative strength of tandem promoters for the antibiotic-resistance genes of several integrons[END_REF][START_REF] Jove | Inverse correlation between promoter strength and excision activity in class 1 integrons[END_REF]. Importantly, all known integron integrases are regulated by the SOS response [START_REF] Guerin | The SOS response controls integron recombination[END_REF][START_REF] Cambray | Prevalence of SOS-mediated control of integron integrase expression as an adaptive trait of chromosomal and mobile integrons[END_REF], which highlights the integron as an evolutionary tool containing a pool of unexpressed genes able to be recombined and expressed when needed, i.e. in response to stress. The SOS control of integrase expression not only means that numerous rearrangements may take place within the chromosomal integrons when they are present, but also that plasmid-borne integrases are likely to be induced when their host's SOS response is triggered. To date, hundreds of cassettes encoding resistance to antibiotics have been characterized in integrons [START_REF] Partridge | Gene cassettes and cassette arrays in mobile resistance integrons[END_REF]. The induction of the integrase by SOS also explains how resistance and adaptation genes can be recruited in such structures during stressful growth, and shows the power of this structure coupled to SOS in the defense of bacteria harboring integrons.

-Share.

We saw earlier that HGT induces SOS. In turn, SOS induces HGT and consequently induces the transfer of genetic information, as it was mentioned for the dissemination of virulence determinants (section II-2-4). It was found for instance that SOS induction triggers response is induced [START_REF] Beaber | SOS response promotes horizontal dissemination of antibiotic resistance genes[END_REF]. It is thought that the ICE-encoded repressor, SetR, undergoes autoproteolysis in the presence of the ssDNA-RecA nucleofilament similarly to

LexA. ICEs such as SXT are self-transmissible bacterial mobile elements that play a major role in the dissemination of antibiotic resistance genes in bacterial populations. They transfer by conjugation in a process similar to that of many conjugative plasmids, and their transfer was shown to induce the SOS response in recipients to the same extent as was observed for conjugative plasmids (Baharoglu et al., 2010). In those terms, the SOS response is a mean for bacteria not only to survive or change, but also to share information with neighboring cells.

III -Fine tuning of SOS induction: attaining balance

-Bacteria can temper their SOS induction

Not all ssDNA induces SOS. In an original recent study, it was observed in growing E.

coli using immunofluorescence microscopy that not all ssDNA formed after antibiotic treatment induces SOS [START_REF] Kohiyama | Trashing of single-stranded DNA generated during processing of arrested replication fork in E. coli[END_REF]. This means that bacteria have a way of insuring genome stability by neutralizing chromosomal ssDNA formed after fluoroquinolone treatment, preventing SOS induction as long as its induction is not required.

Mechanisms actively preventing RecA nucleofilament formation on ssDNA exist. One of them is through the action of RecX. The recX gene is located downstream of recA in the E.

coli chromosome and was proposed by Fuchs and colleagues to regulate RecA (Pages et al., 2003). RecX actually possesses an affinity for RecA and inhibits both its recombinase and coprotease functions without interacting with ssDNA or double-stranded DNA [START_REF] Stohl | Escherichia coli RecX inhibits RecA recombinase and coprotease activities in vitro and in vivo[END_REF]. RecX was found to destabilize ssDNA-RecA nucleofilaments in log-phase cells in a genetic context where RecA was over-expressed [START_REF] Massoni | Factors limiting SOS expression in log-phase cells of Escherichia coli[END_REF]. Another protein that turns off the SOS responses through inhibition of the RecA coprotease is DinI [START_REF] Yasuda | Inhibition of Escherichia coli RecA coprotease activities by DinI[END_REF]. A higher mutation frequency was observed in an E. coli strain deleted for the dinI gene after treatment with the SOS-inducing agent MMC. In vitro studies suggest that, conversely to RecX, DinI does not prevent RecA nucleofilament assembly but stabilizes it, thus "hiding" ssDNA [START_REF] Lusetti | The DinI and RecX proteins are competing modulators of RecA function[END_REF]. DinI and RecX are themselves under the control of the SOS response and affect the stability of the RecA filament and may thus participate in regulating Another protein able to antagonize RecA is UvrD, which is also induced by SOS and involved in the last steps of NER [START_REF] Lestini | UvrD controls the access of recombination proteins to blocked replication forks[END_REF][START_REF] Centore | Induction of competence for genetic transformation by antibiotics: convergent evolution of stress responses in distant bacterial species lacking SOS?[END_REF].

Furthermore, when DinB (Pol IV) is over-produced, the active TLS polymerase Pol IV can impede replication fork progression in such a way that fork arrest does not lead to additional SOS induction [START_REF] Mori | Escherichia coli DinB inhibits replication fork progression without significantly inducing the SOS response[END_REF].

Finally, "Trashing", which consists in a sequestration of genotoxic ssDNA observed in vivo in E. coli cells may represent a new facet of the regulation of the SOS response [START_REF] Kohiyama | Trashing of single-stranded DNA generated during processing of arrested replication fork in E. coli[END_REF]. In this case, ssDNA is somewhat "hidden" from RecA and no induction of the SOS response takes place. Bacteria have thus developed strategies to attenuate SOS to decrease fitness cost and more importantly to mutate less in order to survive.

-Decreasing the fitness cost of SOS induction

Apart from the evolution of bacterial resistance described in section II-2, moderate SOS induction is also involved in the conservation of already existent multiple resistances by the bacteria through the reduction of the fitness cost. For instance, bacteria that show slightly increased frequencies of mutation and harbor antibiotic resistances are found in greater proportions in the commensal flora of cystic fibrosis patients subjected to prolonged antibiotic treatment [START_REF] Gustafsson | Bacteria with increased mutation frequency and antibiotic resistance are enriched in the commensal flora of patients with high antibiotic usage[END_REF]. A recent report even proposes that upon acquisition of resistance (to a β-lactam in this case) E. coli can reorganize its entire metabolic network in order to reduce the fitness costs associated with the acquisition of this resistance [START_REF] Handel | Compensation of the Metabolic Costs of Antibiotic Resistance by Physiological Adaptation in Escherichia coli[END_REF]. The authors observed there that the SOS response itself was down-regulated in response to the acquisition of the resistance. SOS induction thus has a fitness cost better to avoid if the induction is unnecessary.

It also was mentioned in section I-3 that the entry of conjugative plasmids into a recipient cell induces the SOS response. The exceptions to this are the plasmids carrying the psiB (protein for SOS inhibition) gene. In fact, some narrow host range conjugative plasmids harbor this gene which is transferred early during conjugation and which inhibits induction of the SOS response in the recipient cell [START_REF] Bagdasarian | PsiB, and anti-SOS protein, is transiently expressed by the F sex factor during its transmission to an Escherichia coli K-12 recipient[END_REF], probably by binding to RecA [START_REF] Petrova | An SOS Inhibitor that Binds to Free RecA Protein: The PsiB Protein[END_REF]. The advantage of this could be to avoid inducing a stress response in the host: as narrow host range plasmid can replicate only in a small number of hosts they may have evolved to prevent unnecessary mutations and fitness costs.

-Attenuate SOS induction to mutate less and survive

In several reports, intermediate levels of SOS induction (for instance in response to sub-MICs of antibiotics) were found to be a potent strategy of bacteria in order to become persistent (see section II-2) or acquire spontaneous mutations that allow them to survive (see section II-2). It was also observed in E. coli that the mismatch repair system tends to attenuate the appearance of mutations during UV-induced SOS by removing those introduced during by the UmuD' 2 C (PolV) translesion polymerase [START_REF] Belov | The role of the bacterial mismatch repair system in SOS-induced mutagenesis: a theoretical background[END_REF].

We can speculate that bacteria use the SOS response and its mutagenic influence as a "last resort", avoiding its induction when other mechanisms are sufficient to repair the damaged DNA [START_REF] Delmas | Cellular response to horizontally transferred DNA in Escherichia coli is tuned by DNA repair systems[END_REF].

IV -SOS and other stress responses

We described how SOS is linked with transcription-related insults to DNA. SOS is actually connected with various stress responses, highlighting that responses to these various stresses are integrated into a larger network ensuring survival of the bacterial cells.

-Cell wall stress

The most straightforward example of a connection between cell wall stress and SOS is the effect of β-lactams on bacteria: β-lactams induce the SOS response and prophage induction in S. aureus [START_REF] Maiques | beta-lactam antibiotics induce the SOS response and horizontal transfer of virulence factors in Staphylococcus aureus[END_REF]) and E. coli [START_REF] Wadhawan | A component of gamma-radiation-induced cell death in E. coli is programmed and interlinked with activation of caspase-3 and SOS response[END_REF]. β-lactams actually induce the SOS response by triggering a cell wall stress through the DpiAB twocomponent system [START_REF] Miller | SOS response induction by beta-lactams and bacterial defense against antibiotic lethality[END_REF].

In the absence of β-lactams, SOS induction by cell wall stress through the DpiAB system can also be observed by inactivating the genes coding for components of the cell membrane (such as penicillin binding proteins or PBP) [START_REF] Miller | SOS response induction by beta-lactams and bacterial defense against antibiotic lethality[END_REF]. Furthermore, the RpoE envelope stress response sigma factor of E. coli is also required for the increase in frequency of stress-induced mutations through formation of DSBs [START_REF] Gibson | The sigma(E) stress response is required for stress-induced mutation and amplification in Escherichia coli[END_REF]. All of these observations point to a link between cell wall stress and SOS induction.

One consequence of this is that SOS, in conjunction with the DpiAB system, confers β-lactam resistance by transiently halting cell division [START_REF] Miller | SOS response induction by beta-lactams and bacterial defense against antibiotic lethality[END_REF]. Once again, we observe that antibiotics trigger the bacterial stress response, which in turns allows the bacterial cell to resist to this external stress. According to recent reports, the resistance to β- TCA cycle in S. aureus [START_REF] Keaton | Exposure of Clinical MRSA Heterogeneous Strains to beta-Lactams Redirects Metabolism to Optimize Energy Production through the TCA Cycle[END_REF], Plata et al., 2013), which implies a link with oxidative stress.

-Oxidative stress.

In fact, reactive oxygen species (O 2 -, H 2 O 2 , OH -) formed during oxidative stress have the potential to damage DNA, and damaged DNA is a potent inducer of the SOS response.

Our group very recently showed that sub-MICs of AGs lead to the incorporation of oxidized guanine in DNA, suggesting the occurrence of oxidative stress at concentrations 100-fold below the MIC, a concentration at which no killing is observed. Subsequently, sub-MICs AGs mediate induction of the SOS response mostly through oxidized guanine incorporation in DNA (Baharoglu et al., 2013). Since ROS can damage DNA and proteins and induce mutagenesis [START_REF] Mcbride | Mutagenic Spectrum Resulting from DNA Damage by Oxygen Radicals[END_REF][START_REF] Nunoshiba | Role of iron and superoxide for generation of hydroxyl radical, oxidative DNA lesions, and mutagenesis in Escherichia coli[END_REF], we proposed these as the missing links between sub-MIC antibiotic treatment and guanine oxidation.

The link between bactericidal antibiotics, ROS formation and cell death has lately been subject to debate. In order to relieve possible confusion, it may be worth mentioning here that the above-described connection between ROS and SOS happens in conditions where ROS are created in the bacterial cell. For instance, we know that in the presence of sub-MICs of antibiotics ROS are formed in V. cholerae and not in E. coli (Baharoglu et al., 2013). On the other hand, striking studies presented ROS formation as the key step leading to cell death by β-lactams, FQs and AGs [START_REF] Kohanski | A common mechanism of cellular death induced by bactericidal antibiotics[END_REF], Kohanski et al., 2010). This study by Kohanski et al. suggests that all bactericidal antibiotics, regardless of their cellular target, have the potential to induce ROS formation, which kills bacteria. Subsequent studies challenged this hypothesis as no cell death due to ROS formation occurred using these antibiotics in different experimental conditions [START_REF] Keren | Killing by bactericidal antibiotics does not depend on reactive oxygen species[END_REF][START_REF] Liu | Cell death from antibiotics without the involvement of reactive oxygen species[END_REF].

Finally, a recent report elegantly demonstrates that in E. coli it is not ROS that kill bacteria upon AG treatment but rather increased AG uptake due to differential intracellular iron levels and synthesis of iron-sulfur clusters [START_REF] Ezraty | Fe-S cluster biosynthesis controls uptake of aminoglycosides in a ROS-less death pathway[END_REF]. In these latter studies (Kohanski et al., 2007[START_REF] Ezraty | Fe-S cluster biosynthesis controls uptake of aminoglycosides in a ROS-less death pathway[END_REF][START_REF] Keren | Killing by bactericidal antibiotics does not depend on reactive oxygen species[END_REF][START_REF] Liu | Cell death from antibiotics without the involvement of reactive oxygen species[END_REF], antibiotics were used at lethal concentrations because the lethality of antibiotics was what the authors wanted to address. Conversely, in the study about ROS formation and SOS (Baharoglu et al., 2013) concentrations 100-fold below the MIC were used. Hence, these studies differ in the fact that The fact that low doses of antibiotics can induce SOS through ROS formation in certain species like V. cholerae, Klebsiella pneumoniae and Photorhabdus luminescens, might indicate that some species overcome their poorly efficient protection system against oxidative stress by being more easily capable of modifying their gene expression patterns [START_REF] Mcbride | Mutagenic Spectrum Resulting from DNA Damage by Oxygen Radicals[END_REF][START_REF] Nunoshiba | Role of iron and superoxide for generation of hydroxyl radical, oxidative DNA lesions, and mutagenesis in Escherichia coli[END_REF].

In the same line of thought, the DinF protein belonging to the SOS regulon was found to be involved in response to oxidative stress in E. coli [START_REF] Rodriguez-Beltran | The Escherichia coli SOS gene dinF protects against oxidative stress and bile salts[END_REF]

-General stress.

SOS and RpoS were suggested to be complementary mechanisms in response to certain stresses. RpoS, the stationary phase sigma factor, is induced in response to various stresses during the exponential growth phase and increases resistance to stress in E. coli (Merrikh et al., 2009, Merrikh et al., 2009). For instance, and similarly to the SOS response, the RpoS regulon can also be induced during oxidative stress as well as cell wall stress [START_REF] Allen | Impact of hydroxyl-and superoxide anion-based oxidative stress on logarithmic and stationary phase Escherichia coli O157:H7 stress and virulence gene expression[END_REF][START_REF] Mika | Targeting of csgD by the small regulatory RNA RprA links stationary phase, biofilm formation and cell envelope stress in Escherichia coli[END_REF]. Genes expressed following the induction of the RpoS regulon, namely catalases (KatE, KatG) and iron chelators, protect cells from ROS-related DNA damage such as DSBs, which are SOS inducers. The link between the SOS and RpoS responses lies in the fact that both can be considered as mechanisms providing bacteria with means to survive DNA damage [START_REF] Shee | What limits the efficiency of doublestrand break-dependent stress-induced mutation in Escherichia coli?[END_REF]. Other facts linking SOS and RpoS exist:

for example both regulate the dinB gene, which encodes the TLS polymerase Pol IV [START_REF] Kim | Roles of chromosomal and episomal dinB genes encoding DNA pol IV in targeted and untargeted mutagenesis in Escherichia coli[END_REF][START_REF] Layton | Error-prone DNA polymerase IV is controlled by the stressresponse sigma factor, RpoS, in Escherichia coli[END_REF]. Antibiotic-induced mutagenesis involves SOS-dependent dinB induction [START_REF] Kohiyama | Trashing of single-stranded DNA generated during processing of arrested replication fork in E. coli[END_REF] but also induction mediated by RpoS [START_REF] Henle | Formation, prevention, and repair of DNA damage by iron/hydrogen peroxide[END_REF] or NusA [START_REF] Cohen | The transcription elongation factor NusA is required for stress-induced mutagenesis in Escherichia coli[END_REF], a component of the RNA polymerase complex that interacts with DinB. In this sense, RpoS and SOS can also be thought of as complementary mechanisms that protect bacteria from DNA damage: when RpoS is not sufficient, SOS takes over.

-Nutrient stress

A connection between nutrient stress and SOS is also conceivable. For instance, cAMP-dependent SOS induction and mutagenesis was first observed in resting E. coli populations [START_REF] Taddei | cAMP-dependent SOS induction and mutagenesis in resting bacterial populations[END_REF]. cAMP in complex with the CRP protein regulates a set of genes involved in the response to carbon source stress, called carbon catabolite regulation.

More recently, it was found that the cAMP-CRP complex represses SOS-mediated mutations in stationary cell cultures [START_REF] Macphee | Catabolite repression of SOS-dependent and SOSindependent spontaneous mutagenesis in stationary-phase Escherichia coli[END_REF]. However the mechanism of such a regulation remains to be elucidated. cAMP-CRP-dependent induction of SOS has also been observed in E. coli cells starved for arginine, but only when these cells resume growth [START_REF] Janion | Induction of the SOS response in starved Escherichia coli[END_REF]. The authors propose here that these cells accumulate DNA damage that induces SOS upon replication in a yet undiscovered mechanism implicating carbon catabolite control.

V -SOS-like responses

As described above, transformation is a mechanism of HGT that relies on ssDNA uptake and processing [START_REF] Dubnau | DNA uptake in bacteria[END_REF]. Transformation occurs when a bacterial cell reaches a competent state rendering it capable of taking up external DNA present in its environment.

Several mechanisms, such as special growth conditions or stress, lead to the induction of competence for natural transformation in B. subtilis and Streptococcus pneumoniae [START_REF] Claverys | The genetic transformation machinery: composition, localization, and mechanism[END_REF]. Competence has been suggested to be a stress response that could substitute for the SOS response in some bacterial species that lack an SOS regulon but in which the DNA repair genes are part of the competence regulon (for a review see [START_REF] Centore | Induction of competence for genetic transformation by antibiotics: convergent evolution of stress responses in distant bacterial species lacking SOS?[END_REF]).

For instance in S. pneumoniae which lacks LexA, it was found that AGs, FQs and MMC induce competence and RecA, as well as the rate of genetic exchange in response to antibiotics, which is reminiscent of the E. coli SOS response [START_REF] Prudhomme | Antibiotic stress induces genetic transformability in the human pathogen Streptococcus pneumoniae[END_REF].

However, recent data tone down this view: in S. thermophilus which carries the LexA-like repressor HdiR, competence and SOS were shown to be antagonistic mechanisms [START_REF] Boutry | SOS response activation and competence development are antagonistic mechanisms in Streptococcus thermophilus[END_REF]. In this bacterium, SOS-inducing agents induce the SOS regulon genes such as RecA but decrease cellular transformability. As a corollary, induction of competence negatively affects DNA repair under these circumstances. In V. cholerae, SOS-inducing agents do not induce competence either [START_REF] Baharoglu | Transformation-induced SOS regulation and carbon catabolite control of the V. cholerae integron integrase: connecting environment and genome plasticity[END_REF]. However, DNA uptake during competence does induce SOS. Nevertheless, transformation seems to be induced in response to stress in many bacteria [START_REF] Centore | Induction of competence for genetic transformation by antibiotics: convergent evolution of stress responses in distant bacterial species lacking SOS?[END_REF], suggesting it as an alternative to SOS induction in several cases. An SOS-like response was also reported in Acinetobacter baumanii, where DNA damage induces genes involved in response to DNA damage, namely recA, TLS polymerases and NER genes [START_REF] Norton | Antibiotic resistance acquired through a DNA damage-inducible response in Acinetobacter baumannii[END_REF]. However, the regulation of this SOS response does not involve LexA, which is absent from the A. baumanii genome. Nevertheless, induction of this stress response is responsible for damage repair and increase of mutation frequencies leading to antibiotic resistance acquisition, as it happens for E. coli with SOS induction. The increased mutation frequency was recently found to be the result of the A. baumanii TLS polymerase UmuDAb which recognizes palindromic sequences at the promoters of 8 different DNA repair genes and TLS polymerases and regulates their expression in a RecA-dependent manner [START_REF] Aranda | Novel autoproteolytic and DNA-damage sensing components in the bacterial SOS response and oxidized methylcytosine-induced eukaryotic DNA demethylation systems[END_REF].

VI -Strategies to inhibit SOS in the battle against bacterial resistance

In the search for compounds that can potentiate the effect of antibiotics on bacteria, an engineered bacteriophage that suppresses the SOS response by over-expressing a noncleavable LexA repressor has also been reported to enhance killing by quinolones, AGs and β-lactams in E. coli, to reduce the number of resistant bacteria that arise from antibiotic treatment and to increase survival of infected mice [START_REF] Lu | Engineered bacteriophage targeting gene networks as adjuvants for antibiotic therapy[END_REF]. According to the authors, these observations would be the result of disabling DNA damage repair. Such phages could be used in combination with antibiotics as adjuvants that suppress SOS induction and sensitize the bacterial cell to DNA damage. Another type of antimicrobial molecule was recently identified as a repressor of RecA expression: the aminocoumarins. The use of these gyrase inhibitors prevented SOS induction and decreased mutation frequency and recombination even in the presence of FQs in S. aureus [START_REF] Schroder | Opposing effects of aminocoumarins and fluoroquinolones on the SOS response and adaptability in Staphylococcus aureus[END_REF]. Another approach is based on inhibition of RecA expression by engineered artificial small RNAs that are complementary to the recA mRNA [START_REF] Sharma | Knockdown of recA gene expression by artificial small RNAs in Escherichia coli[END_REF]. The use of such sRNAs resulted in an increased sensitivity of E. coli to FQs in laboratory conditions. Finally, RNase E was proposed as a possible target in order to prevent SOS induction because inactivation of RNase E expression in E. coli impedes SOS induction by MMC [START_REF] Manasherob | Ribonuclease E modulation of the bacterial SOS response[END_REF].

A recent review discusses various steps in food processing which trigger SOS induction in bacteria and the impact on food spoilage (van der Veen & Abee, 2011). As depicted in this review, SOS is a transient but very strong stress response used by bacteria to increase their chances to adapt to changing environments and to survive. This is synthesized in the graphical abstract. The stress signal can be a genotoxic one, such as during direct exposure to DNA-damaging agents, but it appears here that many stresses causing changes in a given bacterial lifestyle can be the origin of such a stress. SOS induction can thus be seen as a bacterial adaptation mechanism, which has to be tightly controlled by bacteria in order to prevent a decrease of fitness in conditions where it is not needed. It can be conceived to use SOS modulation as a weapon against bacteria, through the adoption of better policies of antibiotic usage and food processing to avoid SOS-dependent adaptation and resistance of bacteria. *: even though the two LexA paralogues do not appear to play a role in the radioresistance of D. radiodurans [START_REF] Narumi | The LexA protein from Deinococcus radiodurans is not involved in RecA induction following gamma irradiation[END_REF] [START_REF] Jolivet | Limited concentration of RecA delays DNA double-strand break repair in Deinococcus radiodurans R1[END_REF], several studies point to a role of RecA recruitment at DNA lesions and intracellular LexA levels [START_REF] Satoh | Down-regulation of radioresistance by LexA2 in Deinococcus radiodurans[END_REF][START_REF] Satoh | The role of Deinococcus radiodurans RecFOR proteins in homologous recombination[END_REF]. Algorithm-based studies identified a conserved sequence related to the Bacillus subtilis LexA box upstream of the known SOS-regulated genes [START_REF] Khan | Conservation of the LexA repressor binding site in Deinococcus radiodurans[END_REF]. Y: C or T; R: A or G; W: A or T; D: not C; B: not A; N: any base. [START_REF] Helmrich | Transcription-replication encounters, consequences and genomic instability[END_REF]. Codirectional collisions may happen because of the difference of velocity of the replisome and the transcription complex, and lead to DSB formation [START_REF] Dutta | Linking RNA polymerase backtracking to genome instability in E. coli[END_REF]. Head-on collisions occur when transcription and replication progress in opposite directions. Both types of collisions cause DSB formation through either R-loop formation or topological stress, if [START_REF] Wimberly | R-loops and nicks initiate DNA breakage and genome instability in non-growing Escherichia coli[END_REF]. Elongating RNA polymerase (RNAP) can stall upon encounter with a DNA lesion or bulky protein complexes. In this case, transcribed RNA can anneal to the template DNA forming a structure called R-loop. R-loops are another type of SOS inducers as described in section I. R-loops can lead to re-priming of a replication fork. If the re-primed replication fork encounters a nick, it can stall and lead to DSBs (as in panel A).

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Figure 1 .Figure 2 .

 12 Figure 1. Simplified representations of DNA repair pathways induced by SOS (described in the introduction section). HR, NER and TLS are induced during the SOS response. HR: Homologous Recombination. Single strand nicks (gaps) are transformed into larger gaps by the RecJ exonuclease. Gaps are recognized by RecFOR presynaptic proteins. Double strand breaks (DSB) are recognized by the presynaptic RecBCD exonuclease/helicase complex. RecFOR/RecBCD recruit RecA to initiate homologous recombination through strand invasion with the sister chromosome, usually resulting in mutation free repair. DSB repair results in the formation of a replication fork. NER: Nucleotide Excision Repair. The UvrAB complex recognizes the DNA lesion; UvrC proceeds with a double incision on both sides of the lesion and the ssDNA carrying the lesion is removed by the UvrD helicase. DNA polymerase I (Pol I) resynthesizes the missing DNA and the ligase ligates the newly synthesized DNA to the template, usually resulting in mutation free repair. If the SOS inducing signal persists, translesion synthesis (TLS) polymerases are induced. In the absence of TLS, the replicative DNA polymerase (Pol III) cannot replicate damaged DNA, leading to fork stalling. TLS polymerases (Pol IV, Pol V) can replicate damaged DNA in a mutagenic manner. Yellow stars represent DNA lesions. 258x234mm (300 x 300 DPI)

  TLS): the more numerous the initial amount of lesions, the stronger the genotoxic signal and the more genes from the SOS regulon are induced. umuD and umuC are induced later. Similarly to LexA, UmuD undergoes proteolytic cleavage catalyzed by the RecA nucleofilament[START_REF] Nohmi | RecA-mediated cleavage activates UmuD for mutagenesis: mechanistic relationship between transcriptional derepression and posttranslational activation[END_REF]. Cleaved UmuD (named UmuD') becomes activated and, together with UmuC, forms the translesion synthesis DNA polymerase UmuD' 2 C, or Pol V. PolV proceeds with DNA replication on damaged DNA by incorporating any base accross from the DNA lesion that the proof-reading proficient Pol III cannot replicate. Other TLS polymerases exist and, like Pol V, allow the replication of damaged DNA in a mutagenic manner: these are the DNA polymerases Pol II (polB)(Pages

  template in E

  through DNA damage or through replication arrest. The fluoroquinolone (FQ) family of antibiotics which causes replication arrest by blocking DNA

  of SOS are one of the factors contributing to the acquisition of multiple resistances and adaptation factors by bacteria.Moreover, the effects of sub-MICs of antibiotics from different families -such as antibiotics that target translation and not DNA (aminoglycosides, chloramphenicol and tetracycline) -on the SOS response was further addressed. These antibiotics are not expected

  and induction of the SOS response. RecN is an SMC (structural maintenance of the chromosome) family protein induced by SOS, underlining the significance of the SOS response in the repair of lethal chromosomal DSBs.

  involved in HR. Hence, one of the consequences of this SOS induction is to increase intrachromosomal recombination of homologous DNA sequences after DSB formation. This was observed for instance in E. coli through facilitated reconstitution of a functional lacZ gene from the fragments lacZ' and 'lacZ flanked by homologous regions in conditions inducing

A

  recent study achieved mathematical modeling of the link between DNA damage after UV irradiation, SOS induction and mutation frequency by measuring the quantity of the TLS polymerase UmuD' 2 C (Pol V) and corresponding mutation frequencies in E. coli(Ni et

  and adaptation genes. It was described for instance that SOS induction after quinolone treatment could in turn induce the expression of plasmid-borne quinolone resistance determinants in Enterobacteria[START_REF] Da Re | The SOS response promotes qnrB quinolone-resistance determinant expression[END_REF]. Resistance to

  It was mentioned earlier how SOS can be used by bacteria to turn external aggressions in their favor. The examples given were that of resistance to high pressure or to antibiotics conferred by mutations acquired after SOS induction. In the same line of thought, increased antibiotic can lead to the development of resistance to other classes of antibiotics through SOS-mediated integron rearrangements. Hocquet and colleagues show that metronidazole treatment of a patient infected with P. aeroginosa induces the SOS response

  integrating conjugative elements (ICEs) from a donor to a recipient cell. An example of this is the transfer of the V. cholerae ICE SXT, in which the two main ICEencoded transcriptional activators SetC and SetD are de-repressed when the host's SOS

  SOS induction is synergistic with alterations in the cell wall and in the

  lethality or only SOS induction by antibiotics through ROS formation in non-lethal conditions.

Figure 1 .

 1 Figure legendsFigure 1. Simplified representations of DNA repair pathways induced by SOS (described in the introduction section). HR, NER and TLS are induced during the SOS response. HR: Homologous Recombination. Single strand nicks (gaps) are transformed into larger gaps by the RecJ exonuclease. Gaps are recognized by RecFOR presynaptic proteins. Double strand breaks (DSB) are recognized by the presynaptic RecBCD exonuclease/helicase complex.RecFOR/RecBCD recruit RecA to initiate homologous recombination through strand invasion with the sister chromosome, usually resulting in mutation free repair. DSB repair results in the formation of a replication fork. NER: Nucleotide Excision Repair. The UvrAB complex recognizes the DNA lesion; UvrC proceeds with a double incision on both sides of the lesion and the ssDNA carrying the lesion is removed by the UvrD helicase. DNA polymerase I (Pol I) resynthesizes the missing DNA and the ligase ligates the newly synthesized DNA to the template, usually resulting in mutation free repair. If the SOS inducing signal persists, translesion synthesis (TLS) polymerases are induced. In the absence of TLS, the replicative DNA polymerase (Pol III) cannot replicate damaged DNA, leading to fork stalling. TLS polymerases (Pol IV, Pol V) can replicate damaged DNA in a mutagenic manner. Yellow stars represent DNA lesions.

Figure 2 .

 2 Figure 2. Origins of ssDNA inducing SOS. A. Replication fork stalling often leads to spontaneous ssDNA nicks. These breaks are eventually transformed into double strand breaks (DSBs) when replication restarts, and DSBs are potent inducers of SOS as described in section I. B. Replication transcription collisions. Adapted from[START_REF] Helmrich | Transcription-replication encounters, consequences and genomic instability[END_REF]. Codirectional collisions may happen because of the difference of velocity of the replisome and the transcription complex, and lead to DSB formation[START_REF] Dutta | Linking RNA polymerase backtracking to genome instability in E. coli[END_REF]. Head-on collisions occur when transcription and replication progress in opposite directions. Both types of collisions cause DSB formation through either R-loop formation or topological stress, if

  insufficient. C. Transcription stalling. Adapted from

  ssDNA substrate for RecA. RecFOR recognizes DNA nicks and gaps, and recruits RecA to this ssDNA patch. RecA binds ssDNA in the form of a nucleofilament which catalyzes the auto-proteolysis of the repressor LexA. LexA represses the genes belonging to

	formation of an
	F o
	r
	P
	e e r
	R e v i e w
	2

. Briefly, RecA is recruited on ssDNA by presynaptic complexes RecBCD or RecFOR. RecBCD recognizes double strand DNA breaks (DSB) or double strand ends (DSE). Its helicase and nuclease activities result in the

  , or CcdAB from the F

	plasmid which induces SOS through poisoning of the gyrase
	F o
	r
	P
	e e r
	R e v i e w
	14

  : in fact, expression of DinF protects against bile salts and H 2 O 2 by decreasing the effects of ROS and protein carbonylation, showing that SOS and the oxidative stress response can be complementary mechanisms in bacterial survival.

Table 1 : LexA box sequences identified accross different bacterial species. Organism LexA box consensus 5'-3' Method of determination References GRAM negatives Beta-and Gamma- proteobacteria

 1

		CTGTN 8 ACAG	in silico	(Erill et al., 2003)
	E. coli TACTGTATATATATACAGTA in vitro, in vivo	(Fernandez De Henestrosa
				et al., 2000) (Wade et al.,
				2005)
	Alpha-proteobacteria
	Rhodobacter	GTTCN 7 GTTC	in vitro	(Fernandez de Henestrosa et
	sphaeroides			al., 1998)
	Rhizobium and	GAACN 7 GTAC	in vitro, in vivo	(Tapias & Barbe, 1998)
	Agrobacterium
	Cyanobacteria	RGTACN 3 DGTWCB	in vitro	(Mazon et al., 2004)
	Spirocheate

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Acknowledgements

We thank Geneviève Garriss and Jason Bland for the helpful reading of the manuscript. Our work was supported by the Institut Pasteur, the Centre National de la Recherche Scientifique (CNRS-UMR3525); the European Union Seventh Framework Programme (FP7-HEALTH-2011-single-stage) "Evolution and Transfer of Antibiotic Resistance" (EvoTAR); and the French Government's Investissement d'Avenir program Laboratoire d'Excellence "Integrative Biology of Emerging Infectious Diseases" (grant ANR-10-LABX-62-IBEID). ZB was supported by a DIM Malinf postdoctoral fellowship (Conseil régional d'Île-de-France) and EvoTAR.

The authors declare no conflict of interest.