DdiA, an XRE family transcriptional regulator, regulates a LexA-independent DNA damage response in Myxococcus xanthus

Abstract

Repair of DNA damage is essential for genome integrity. DNA damage elicits a DNA damage response (DDR) that includes error-free and error-prone, i.e. mutagenic, repair. The SOS response is a widely conserved system in bacteria that regulates the DDR and depends on the recombinase RecA and the transcriptional repressor LexA. However, RecA/LexA-independent DDRs have been identified in several bacterial species. Here, using a whole-cell, label-free quantitative proteomics approach, we map the proteomic response in Myxococcus xanthus to mitomycin C treatment and the lack of LexA. In doing so, we confirm a LexA-independent DDR in M. xanthus. Using a candidate approach, we identify DdiA, a transcriptional regulator of the XRE family, and demonstrate that it regulates a subset of the LexA-independent DDR genes. ddiA is expressed heterogeneously in a subpopulation of cells in the absence of exogenous genotoxic stress and reversibly induced population-wide in response to such stress. DdiA, indirectly or directly, activates the expression of dnaE2, which encodes the DnaE2 error-prone DNA polymerase, and inhibits the expression of recX, which encodes RecX, a negative regulator of RecA. Accordingly, the {Delta}ddiA mutant has a lower mutation frequency than the wild-type but also a fitness defect, suggesting that DdiA mediates a trade-off between fitness and mutagenesis. We speculate that the DdiA-dependent response is tailored to counter replication stress, thereby preventing the induction of the complete RecA/LexA-dependent DDR in the absence of exogenous genotoxic stress. ImportanceDNA damage repair is essential for genome integrity and depends on the DNA damage response (DDR). While the RecA/LexA-dependent SOS response is widely conserved in bacteria, there are also RecA/LexA-independent DDRs. Here, we identify the DNA damage-induced transcriptional regulator DdiA in Myxococcus xanthus and demonstrate that it regulates part of the RecA/LexA-independent DDR. DdiA activates the expression of dnaE2, which encodes the DnaE2 error-prone DNA polymerase, and inhibits the expression of recX, which encodes RecX, a negative regulator of RecA. Because the {Delta}ddiA mutant has a lower mutation frequency than the wild-type but also a fitness defect, we suggest that DdiA mediates a trade-off between fitness and mutagenesis and that the DdiA-dependent DDR is specifically tailored to counter replication stress.