The Function Of COP9 Signalosome CSN^CSN7B Complex In DNA Double Strands Breaks Repair

Mammalian COP9 signalosome(CSN)-controlling～600 ubiquitin ligases targeting～20%of the proteome-exists as two variants containing either CSN7A or CSN7B paralogs,but functional specialization of these complexes remains unknown.Eukaryotic cells have developed complex DNA damage response(DDR)mechanisms to accurately sense and repair DNA,which can be a reason for drug resistance.Mitomycin C(MMC),a frequently used chemotherapeutical drug in cancer therapy,induces DNA damage and apoptosis in tumor cells.It also activates DDR counteracting the effect of chemotherapy.Therefore,understanding DNA repair mechanism is a prerequisite to develop more effective tumor therapies.The COP9 signalosome(CSN)is a component of the DDR pathway by its intrinsic deneddylating and associated kinase activities.We found that knockout of CSN7A or CSN7B is tolerated by mammalian cells,indicating redundant functions in the deneddylation of cullin-RNG 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 yH2AX as well as DNA damage-induced apoptosis.Consistently,live cell 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.