CSN7B Defines a Variant COP9 Signalosome Complex with Distinct Function in DNA Damage Response

Abstract

Mammalian COP9 signalosome (CSN) exists as two variant complexes containing either CSN7A or CSN7B paralogs, but functional specialization of these complexes remains unknown. We found that knockout of CSN7A or CSN7B is tolerated by mammalian cells, indicating redundant functions in the deneddylation of cullin-RING ubiquitin ligases. Nevertheless, CSNCSN7B has a unique function in DNA double strand break (DSB) sensing, being selectively required for ATM-dependent formation of NBS1S343p and γH2AX as well as DNA damage-induced apoptosis. Consistently, live cell confocal microscopy revealed rapid recruitment of CSN7B but not CSN7A to DSBs. Resistance of CSN7B knockout cells to DNA damage is explained by the failure to deneddylate an upstream DSB signaling pathway component. In mice, CSN7B knockout tumors are resistant to DNA damage-inducing chemotherapy. Our loss-of-function study on the role of CSNCSN7B in DNA repair provides a mechanistic underpinning for the poor prognosis of tumors with low CSN7B expression.