CsrA inhibits thymineless death in Escherichia coli lacking the SOS response
Thymineless death (TLD) is the rapid loss of colony-forming ability of bacterial, yeast and human cells starved for thymine, and is the mechanism of action of common cancer chemotherapeutic drugs.  In Escherichia coli, about 10-fold (one log) of the loss of viability during TLD requires the SOS DNA-damage response, specifically the SOS-induced inhibitor of cell division, SulA. An independent RecQ- and RecJ-dependent TLD pathway accounts for an additional roughly one log of TLD, and a third SOS- and RecQ/J-independent TLD pathway was also observed. Although three groups demonstrated or implicated the SOS-response role in TLD, an SOS-deficient mutant strain from an earlier study was paradoxically TLD-proficient. We performed whole-genome resequencing on the SOS-deficient strain with no TLD defect and show that, compared with the SOS-proficient control strain, it contains five mutations other than the SOS-blocking lexA(Ind-) mutation.  We show that one of the additional mutations, csrA, causes TLD sensitivity specifically in SOS-defective strains.  We find that wild-type CsrA inhibits TLD in SOS- or sulA-defective cells, and the hyper-TLD that occurs in csrA- SOS-defective cells occurs via a RecQ-dependent TLD pathway.  We provide a model for how CsrA might inhibit TLD in SOS-deficient, SulA-deficient cells, by modulating nucleotide pools.