Systematic characterization of deubiquitylating enzymes for roles in maintaining genome integrity
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Authors
Nishi, Ryotaro
Wijnhoven, Paul
le, Sage Carlos
Tjeertes, Jorrit
Clague, Michael J
Urbé, Sylvie
Publication Date
2014-09-07Journal Title
Nature Cell Biology
ISSN
1465-7392
Publisher
Nature Publishing Group
Volume
16
Pages
1016-1026
Language
English
Type
Article
Metadata
Show full item recordCitation
Nishi, R., Wijnhoven, P., le, S. C., Tjeertes, J., Galanty, Y., Forment, J., Clague, M. J., et al. (2014). Systematic characterization of deubiquitylating enzymes for roles in maintaining genome integrity. Nature Cell Biology, 16 1016-1026. https://doi.org/10.1038/ncb3028
Abstract
DNA double-strand breaks (DSBs) are perhaps the most toxic of all DNA lesions, with defects in the DNA damage response to DSBs being associated with various human diseases. Although it is known that DSB repair pathways are tightly regulated by ubiquitylation, we do not yet have a comprehensive understanding of how deubiquitylating enzymes (DUBs) function in DSB responses. Here, by carrying out a multi-dimensional screening strategy for human DUBs, we identify several with hitherto unknown links to DSB repair, the G2/M DNA-damage checkpoint and genome-integrity maintenance. Phylogenetic analyses reveal functional clustering within certain DUB subgroups, suggesting evolutionally conserved functions and/or related modes-of action. Furthermore, we establish that the DUB UCHL5 regulates DSB resection and repair by homologous recombination through protecting its interactor, NFRKB, from degradation. Collectively our findings extend the list of DUBs promoting the maintenance of genome integrity, and highlight their potential as therapeutic targets for cancer.
Sponsorship
Cancer Research UK (11224)
Cancer Research UK (A12964)
Wellcome Trust (092096/Z/10/Z)
European Research Council (268536)
Cancer Research UK (A14492)
Identifiers
External DOI: https://doi.org/10.1038/ncb3028
This record's URL: https://www.repository.cam.ac.uk/handle/1810/245708
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