@article{bbd25964af984ab3948b8d4d1da51305,
title = "USP4 Auto-Deubiquitylation Promotes Homologous Recombination",
abstract = "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.",
author = "Paul Wijnhoven and Rebecca Konietzny and Blackford, {Andrew N.} and Jonathan Travers and Kessler, {Benedikt M.} and Ryotaro Nishi and Jackson, {Stephen P.}",
note = "Funding Information: We thank all members of the S.P.J. and B.M.K. laboratories and Jorrit Tjeertes for helpful discussions, and Kate Dry for commenting on the manuscript. We thank Carlos le Sage for help with FLAG-Tev-Strep tag plasmid design and helpful discussions; Matylda Sczaniecka-Clift, Muku Demir, and Julia Coates for help with stable cell line establishment; and Tobias Oelschlaegel for producing GFP-FLAG-MRE11 polyclonal U2OS cells. We also thank Matylda Sczaniecka-Clift and Nicola Geisler for purifying USP4 peptides for antibody production. Research in the S.P.J. laboratory is funded by CRUK Program Grant C6/A11224, the European Community Seventh Framework Program grant agreement no. HEALTH-F2-2010-259893 (DDResponse), and ERC Advanced Grant DDREAM. R.N. was funded by the Daiichi Sankyo Foundation of Life Sciences fellowship and the CRUK Project Grant C6/A14831. 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 in the B.M.K. laboratory performed by R.K. and B.M.K. Publisher Copyright: {\textcopyright} 2015 The Authors.",
year = "2015",
month = nov,
day = "5",
doi = "10.1016/j.molcel.2015.09.019",
language = "English",
volume = "60",
pages = "362--373",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "3",
}