期刊
CELL
卷 176, 期 3, 页码 505-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2018.11.024
关键词
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资金
- Dr. M. and S.G. Adelson Medical Research Foundation
- Israel Science Foundation joint ISF-NSFC Research Program
- Israel Cancer Research Fund
- German-Israeli Foundation for Research and Development [I-65-412.20-2016]
- Deutsche Forschungsgemeinschaft [KFO-286-RP2, KFO-286-CP2, JA2439/1-1, DI1731/2-1]
- Else Kroner-Fresenius Stiftung [2014-A06, 2016_Kolleg.19]
- Deutsche Krebshilfe [1117240]
- Deutsche Krebshilfe (Mildred-Scheel Professorship)
- German Ministry of Education and Research [BMBF 01GM1211B, BMBF e:Med 01ZX1303A, 01ZX1406, BMBF e:Med 01ZX1303, 01ZX1307]
- R+D+I grants from the Spanish Ministry of Economy and Competitivity [SAF2013-43255-P, SAF2016-74855-P]
Genomic instability can be a hallmark of both human genetic disease and cancer. We identify a deleterious UBQLN4 mutation in families with an autosomal recessive syndrome reminiscent of genome instability disorders. UBQLN4 deficiency leads to increased sensitivity to genotoxic stress and delayed DNA double-strand break (DSB) repair. The proteasomal shuttle factor UBQLN4 is phosphorylated by ATM and interacts with ubiquitylated MRE11 to mediate early steps of homologous recombination-mediated DSB repair (HRR). Loss of UBQLN4 leads to chromatin retention of MRE11, promoting non-physiological HRR activity in vitro and in vivo. Conversely, UBQLN4 overexpression represses HRR and favors non-homologous end joining. Moreover, we find UBQLN4 overexpressed in aggressive tumors. In line with an HRR defect in these tumors, UBQLN4 overexpression is associated with PARP1 inhibitor sensitivity. UBQLN4 therefore curtails HRR activity through removal of MRE11 from damaged chromatin and thus offers a therapeutic windowfor PARP1 inhibitor treatment in UBQLN4-overexpressing tumors.
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