Role of the BRCC36 deubiquitylase in DNA damage signaling and DNA repair

Abstract

The RAP80-BRCA1 complex, a DNA damage responsive protein complex, accumulates at the vicinity of DNA double-stand breaks (DSBs) to promote the functionality of genome caretaker BRCA1 in DSB signal transduction and repair processes. The RAP80-BRCA1 complex has capability not only to recognize Lysine-63-Ubiquitin (K63-Ub) polymers, but also exhibits K63-Ub specific deubiquitylase (DUB) activity which is conferred by one of its components, BRCC36. Although the regulatory basis of its DUB activity has been characterized, the requirement and significance of the DUB activity of the RAP80-BRCA1 complex in regulating DNA damage responses (DDRs) has remained largely unknown. As part of our effort to understand how the DUB activity of the RAP80-BRCA1 complex contributes to its role in regulating chromatin responses at DSBs, both RNA interference and genome editing approaches were employed to target BRCC36. Remarkably, we found that BRCC36, in manners that require its DUB activity, is essential to promote the stable accumulation of the RAP80-BRCA1 complex at DNA damage sites. Moreover, we also showed that BRCC36 negatively regulates high-fidelity homology-based DNA repair by limiting excessive DSB end resection. Collectively, our findings establish an important role of the BRCC36 DUB activity in driving the functionality of the RAP80-BRCA1 complex in cellular responses to DNA damage.