A Feedback Regulatory Loop Containing McdR and WhiB2 Controls Cell Division and DNA Repair in Mycobacteria

Cell division must be coordinated with DNA repair, which is strictly regulated in response to different drugs and environmental stresses in bacteria. However, the mechanisms by which mycobacteria orchestrate these two processes remain largely uncharacterized. Here, we report a regulatory loop between two essential mycobacterial regulators, McdR (Rv1830) and WhiB2, in coordinating the processes of cell division and DNA repair. McdR inhibits cell division-associated whiB2 expression by binding to the AATnACAnnnnTGTnATT motif in the promoter region. Furthermore, McdR overexpression simultaneously activates imuAB and dnaE2 expression to promote error-prone DNA repair, which facilitates genetic adaptation to stress conditions. Through a feedback mechanism, WhiB2 activates mcdR expression by binding to the cGACACGc motif in the promoter region. Importantly, analyses of mutations in clinical Mycobacterium tuberculosis strains indicate that disruption of this McdR-WhiB2 feedback regulatory loop influences expression of both cell growth- and DNA repair-associated genes, which further supports the contribution of McdR-WhiB2 regulatory loop in regulating mycobacterial cell growth and drug resistance. This highly conserved feedback regulatory loop provides fresh insight into the link between mycobacterial cell growth control and stress responses. IMPORTANCE Drug-resistant M. tuberculosis poses a threat to the control and prevention of tuberculosis (TB) worldwide. Thus, there is a need to identify the mechanisms enabling M. tuberculosis to adapt and grow under drug-induced stress. Rv1830 has been shown to be associated with drug resistance in M. tuberculosis, but its mechanisms have not yet been elucidated. Here, we reveal a regulatory role of Rv1830, which coordinates cell division and DNA repair in mycobacteria, and rename it McdR (mycobacterial cell division regulator). An increase in McdR levels represses the expression of cell division-associated whiB2 but activates the DNA repair-associated, error-prone enzymes ImuA/B and DnaE2, which in turn facilitates adaptation to stress responses and drug resistance. Furthermore, WhiB2 activates the transcription of mcdR to form a conserved regulatory loop. These data provide new insights into the mechanisms controlling mycobacterial cell growth and stress responses.