USP4 Auto-Deubiquitylation Promotes Homologous Recombination
Kessler, Benedikt M
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Wijnhoven, P., Konietzny, R., Blackford, A., Travers, J., Kessler, B. M., Nishi, R., & Jackson, S. (2015). USP4 Auto-Deubiquitylation Promotes Homologous Recombination. Molecular Cell, 60 362-373. https://doi.org/10.1016/j.molcel.2015.09.019
Repair of DNA double-strand breaks is crucial for maintaining genome integrity and is governed by post-translational modifications such as protein ubiquitylation. Here, we establish that the deubiquitylating enzyme USP4 promotes DNA-end resection and DNA repair by homologous recombination. We also report that USP4 interacts with CtIP and the MRE11-RAD50-NBS1 (MRN) complex and is required for CtIP recruitment to DNA damage sites. Furthermore, we show that USP4 is ubiquitylated on multiple sites including those on cysteine residues and that deubiquitylation of these sites requires USP4 catalytic activity and is required for USP4 to interact with CtIP/MRN and to promote CtIP recruitment and DNA repair. Lastly, we establish that regulation of interactor binding by ubiquitylation occurs more generally among USP-family enzymes. Our findings thus identify USP4 as a novel DNA repair regulator and invoke a model in which ubiquitin adducts regulate USP enzyme interactions and functions.
Research in the S.P.J. laboratory is funded by CRUK Program Grant C6/A11224, CRUK Project Grant C6/A14831 and the European Community Seventh Framework Program grant agreement no. HEALTH-F2-2010-259893 (DDResponse). R.N. was funded by the Daiichi Sankyo Foundation of Life Sciences fellowship. Cancer Research UK Grant C6946/A14492 and Wellcome Trust Grant WT092096 provided core infrastructure funding. S.P.J receives his salary from the University of Cambridge, supplemented by CRUK. The John Fell Fund 133/075 and the Wellcome Trust grant 097813/Z/11/Z funded research performed by B.M.K and R.K..
Cancer Research UK (A18796)
Wellcome Trust (092096/Z/10/Z)
Cancer Research UK (A14492)
External DOI: https://doi.org/10.1016/j.molcel.2015.09.019
This record's URL: https://www.repository.cam.ac.uk/handle/1810/251079
Creative Commons Attribution 4.0 International License
Licence URL: http://creativecommons.org/licenses/by/4.0/
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