The Lys63-deubiquitylating Enzyme BRCC36 Limits DNA Break Processing and Repair.
Multisubunit protein assemblies offer integrated functionalities for efficient cell signal transduction control. One example of such protein assemblies, the BRCA1-A macromolecular complex, couples ubiquitin recognition and metabolism and promotes cellular responses to DNA damage. Specifically, the BRCA1-A complex not only recognizes Lys(63)-linked ubiquitin (K63-Ub) adducts at the damaged chromatin but is endowed with K63-Ub deubiquitylase (DUB) activity. To explore how the BRCA1-A DUB activity contributes to its function at DNA double strand breaks (DSBs), we used RNAi and genome editing approaches to target BRCC36, the protein subunit that confers the BRCA1-A complex its DUB activity. Intriguingly, we found that the K63-Ub DUB activity, although dispensable for maintaining the integrity of the macromolecular protein assembly, is important in enforcing the accumulation of the BRCA1-A complex onto DSBs. Inactivating BRCC36 DUB attenuated BRCA1-A functions at DSBs and led to unrestrained DSB end resection and hyperactive DNA repair. Together, our findings uncover a pivotal role of BRCC36 DUB in limiting DSB processing and repair and illustrate how cells may physically couple ubiquitin recognition and metabolizing activities for fine tuning of DNA repair processes.
From the School of Biomedical Sciences, LKS Faculty of Medicine, and.
Hoi-Man
HM
Ng
the Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
Leizhen
L
Wei
the Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
Li
L
Lan
From the School of Biomedical Sciences, LKS Faculty of Medicine, and the State Key Laboratory of Brain and Cognitive Sciences, University of Hong Kong, L1-46, Laboratory Block, 21 Sassoon Road, Pokfulam, Hong Kong and huen.michael@hku.hk.
Michael S Y
MS
Huen
D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D000072017:Deubiquitinating Enzymes; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D008565:Membrane Proteins; D025801:Ubiquitin; C518017:BRCC3 protein, human; D000072017:Deubiquitinating Enzymes
BRCA1; DNA damage; DNA damage response; DNA repair; ubiquitin; ubiquitin ligase