Germline Mutations in BAP1 Impair Its Function in DNA Double-Strand Break Repair

被引：161

作者：

Ismail, Ismail Hassan ^{[1
,2
]}

Davidson, Riley ^{[1
]}

Gagne, Jean-Philippe ^{[3
]}

Xu, Zhi Zhong ^{[1
]}

Poirier, Guy G. ^{[3
]}

Hendzel, Michael J. ^{[1
]}

机构：

[1] Univ Alberta, Fac Med & Dent, Dept Oncol, Edmonton, AB, Canada

[2] Cairo Univ, Fac Sci, Dept Biophys, Giza, Egypt

[3] Univ Laval, Hotel Dieu Quebec, Canc Res Ctr, Quebec City, PQ, Canada

来源：

CANCER RESEARCH | 2014年 / 74卷 / 16期

关键词：

DAMAGE RESPONSE; HISTONE H2A; BRCA1-ASSOCIATED PROTEIN-1; UBIQUITIN HYDROLASE; TUMOR-SUPPRESSOR; BRCA1; RNF8; UBIQUITYLATION; TRANSCRIPTION; COMPLEX;

D O I：

10.1158/0008-5472.CAN-13-3109

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The BRCA1-associated deubiquitylase BAP1 is mutated in several cancers, most notably mesothelioma and melanoma, where it is thought to promote oncogenesis. In this study, we present evidence that BAP1 functions as part of the DNA damage response (DDR). We found that BAP1 mediates rapid poly(ADP-ribose)-dependent recruitment of the polycomb deubiquitylase complex PR-DUB to sites of DNA damage. Furthermore, we identified BAP1 as a phosphorylation target for the DDR kinase ATM. Functionally, BAP1 promoted repair of DNA double-strand breaks, enhancing cell survival after DNA damage. Our results highlight the importance of ubiquitin turnover at sites of DNA damage, and they provide a mechanism to account for the tumor-suppressive function of BAP1. (C)2014 AACR.

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收藏

页码：4282 / 4294

页数：13

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