Systematic characterization of deubiquitylating enzymes for roles in maintaining genome integrity

被引：118

作者：

Nishi, Ryotaro ^{[1
,2
]}

Wijnhoven, Paul ^{[1
,2
]}

le Sage, Carlos ^{[1
,2
]}

Tjeertes, Jorrit ^{[1
,2
]}

Galanty, Yaron ^{[1
,2
]}

Forment, Josep V. ^{[1
,2
]}

Clague, Michael J. ^{[3
]}

Urbe, Sylvie ^{[3
]}

Jackson, Stephen P. ^{[1
,2
,4
]}

机构：

[1] Univ Cambridge, Wellcome Trust Canc Res UK Gurdon Inst, Cambridge CB2 1QN, England

[2] Univ Cambridge, Dept Biochem, Cambridge CB2 1QN, England

[3] Univ Liverpool, Inst Translat Med, Liverpool L69 3BX, Merseyside, England

[4] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, Cambs, England

来源：

NATURE CELL BIOLOGY | 2014年 / 16卷 / 10期

基金：

英国惠康基金; 欧洲研究理事会;

关键词：

STRAND BREAK REPAIR; DNA-DAMAGE RESPONSE; CHROMATIN-REMODELING COMPLEX; UCH37 DEUBIQUITINATING ENZYME; FANCONI-ANEMIA PATHWAY; HOMOLOGOUS RECOMBINATION; DEPENDENT UBIQUITINATION; PROTEASOME; STABILITY; RNF8;

D O I：

10.1038/ncb3028

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 multidimensional 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.

引用

页码：1016 / 1026

页数：11

共 46 条

[1] A screen for deubiquitinating enzymes involved in the G2/M checkpoint identifies USP50 as a regulator of HSP90-dependent Wee1 stability [J].