Abstracts Category : Other

Role of the BRCC36 deubiquitylase in DNA damage signalingand DNA repair

by Hoi-man Ng

The RAP80-BRCA1 complex, a DNA damage responsiveprotein complex, accumulates at the vicinity of DNA double-standbreaks (DSBs) to promote the functionality of genome caretakerBRCA1 in DSB signal transduction and repair processes. TheRAP80-BRCA1 complex has capability not only to recognizeLysine-63-Ubiquitin (K63-Ub) polymers, but also exhibits K63-Ubspecific deubiquitylase (DUB) activity which is conferred by one ofits components, BRCC36. Although the regulatory basis of its DUBactivity has been characterized, the requirement and significanceof the DUB activity of the RAP80-BRCA1 complex in regulating DNAdamage responses (DDRs) has remained largely unknown. As part ofour effort to understand how the DUB activity of the RAP80-BRCA1complex contributes to its role in regulating chromatin responsesat DSBs, both RNA interference and genome editing approaches wereemployed to target BRCC36. Remarkably, we found that BRCC36, inmanners that require its DUB activity, is essential to promote thestable accumulation of the RAP80-BRCA1 complex at DNA damage sites.Moreover, we also showed that BRCC36 negatively regulateshigh-fidelity homology-based DNA repair by limiting excessive DSBend resection. Collectively, our findings establish an importantrole of the BRCC36 DUB activity in driving the functionality of theRAP80-BRCA1 complex in cellular responses to DNAdamage. published_or_final_version Biomedical Sciences Doctoral Doctor of Philosophy