A RecBCD-like enzyme regulates expression of bacterial defense operons in response to DNA damage

Bacteria must quickly respond to stress signals including bacteriophage (phage) infection, invasion by mobile genetic elements, and other threats. DNA damage is a stress-signaling nexus in bacteria, initiating global responses such as the SOS response and triggering expression of specific defense and immune pathways through DNA damage-sensing transcriptional regulators. Here we identify a three-protein pathway termed Cerberus that senses dsDNA ends that become available during DNA damage or inhibition of the key DNA repair complex RecBCD, and controls expression of an associated defense/immune operon. The central player in Cerberus is a large peptidase-helicase-nuclease fusion protein, CerC, that is architecturally similar to the RecBC complex itself. Upon DNA damage or RecBCD inhibition, CerC binds and unwinds free DNA ends to allosterically activate its fused HExxH metallopeptidase domain. CerC specifically cleaves the adjacently encoded anti-sigma factor CerB to release its cognate sigma factor CerA, allowing CerA to mediate transcription of a defense/immune operon encoded nearby. Cerberus therefore represents a pathway that has co-opted a key DNA repair machine for DNA damage sensing, and linked that activity to transcriptional control through anti-sigma factor cleavage.