DdiA, an XRE family transcriptional regulator, is a co-regulator of the 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 demonstrate a LexA-independent proteomic DDR in M. xanthus. Using a candidate approach, we identify DNA damage-induced protein A (DdiA), a transcriptional regulator of the Xenobiotic Response Element (XRE) family, and demonstrate that it is involved in regulating the abundance of a subset of the LexA-independent DDR proteins. 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 ΔddiA mutant not only 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 a 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 ΔddiA 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 the DdiA-dependent DDR is specifically tailored to counter replication stress.