# Unbridled Integons: A Matter of Host Factors
## 4 Host Factors Influencing the Expression of the Integrase
### Integrase Expression and SOS Response
#### 4.1.2 SOS Response and Antibiotic Induced Stresses  
In most cases, ssDNA originates from double-strand breaks (DSB). Many factors can induce the formation of DSB in bacteria, whether due to external damaging agents or not. In absence of any damaging agent in the medium, it was shown that most of the DSBs stem from topological stress applied on the chromosome or by the formation of R-loops [41]. In the case of DSB due to such intrinsic factors, the SOS response is essential to efficiently repair the DNA damage and allow the cell to resume a normal lifestyle [27]. It was argued that, at lethal doses, the majority if not all antibiotics trigger the SOS response [42; 43]. For the antibiotics directly targeting the synthesis of DNA (trimethoprim/sulfamethoxazole) and the maintenance of the genome (quinolones), this connection is straightforward. For instance, quinolones target topoisomerases of class II (DNA gyrases) and IV. Upon binding to their target, they will block their activity and therefore cause high topological stress that leads quickly to the accumulation of DSB, as mentioned previously. Therefore, quinolones such as ciprofloxacin are potent inducers of the SOS response [38; 44]. Similarly, compounds that alter directly DNA, such as mitomycin that causes T-T cross-links, also efficiently trigger the SOS response [30; 38]. For rifamycin, this blocks the activity of RNAP and therefore transcription; its side effect is to cause RNAP stalling and hence replication-transcription conflicts and formation of R-loops that both lead to high genomic instability [41]. The cascade of events linking the direct effect of the antibiotics and DNA damage can yet be more indirect. \(\beta\)-lactams, which inhibit the synthesis of the peptidoglycan and cause cell-wall damage, were shown to induce the two-component system DpiBA [45]. Induction of this signaling pathway ultimately leads to replication fork arrest and induction of the SOS response. Finally, many bacteria antibiotics targeting protein synthesis such as aminoglycosades are also able to trigger the SOS response [46; 47]. Indeed, because of the coupling of translation and transcription in bacteria, the action of aminoglycosades on translation also alters the transcription rates and causes RNAP stalling, and amino acids miss-incorporation, leading to ROS production and to DNA damage [30]. The SOS regulon is an integrated pathway and will not be activated the same way, or with the same cues, in every species. For instance, as mentioned above, aminoglycoses generally trigger the SOS response in _V. cholerae_ as well as in other species such as _Klebsiella pneumoniae_ and _Pseudomonas luminescens_[48] but not in _E. coli_. Indeed, in _E. coli_ a specific mechanism of control of the oxidative stress response prevents the SOS induction by nongenotoxic antibiotics [48]. Hence, the expression of the integrase upon induction of the SOS response is an ideal adaptive pathway for the cell in the context of antibiotics treatments. In their presence, if the integer contains the adequate resistance cassette but it is out of range of the P\({}_{\text{C}}\) promoter, then the regulation of the integrase by the SOS response takes all its importance. The array will be rearranged at random and quickly generate important diversity in cassette order, on which selection can operate so that the best fitting configuration of array will become advantageous. Thus, resistant clones will emerge at a much higher rate than it would have while counting solely on the mutation rate. This is especially true in the case of combinatorial antibiotic treatments that completely forbid the appearance of resistant clones through mutations only. Integons, because of their modular organization, allow the cell to adapt to multiple stresses, simultaneously providing adaptation \"on demand\" [36].