Inhibition of the DNA damage response by deubiquitinating enzymes

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I reported that OTUB1, a deubiquitinating enzyme, was an inhibitor of DSB-induced chromatin ubiquitination. Surprisingly, we found that OTUB1 suppressed RNF168-dependent poly-ubiquitination independently of its catalytic activity. OTUB1 did so by binding to and inhibiting UBC13, the cognate E2 enzyme for RNF168. This unusual mode of regulation was unlikely to be limited to UBC13 because analysis of OTUB1-associated proteins revealed that OTUB1 bound to E2s of the UBE2D and UBE2E subfamilies. Finally, OTUB1 depletion mitigated the DSB repair defect associated with defective ATM signalling, indicating that pharmacological targeting of the OTUB1-UBC13 interaction might enhance the DNA damage response.