Sobhian Bijan, Shao Genze, Lilli Dana R, Culhane Aedín C, Moreau Lisa A, Xia Bing, Livingston David M, Greenberg Roger A
Dana-Farber Cancer Institute and Department of Genetics and Department of Medicine, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
Science. 2007 May 25;316(5828):1198-202. doi: 10.1126/science.1139516.
Mutations affecting the BRCT domains of the breast cancer-associated tumor suppressor BRCA1 disrupt the recruitment of this protein to DNA double-strand breaks (DSBs). The molecular structures at DSBs recognized by BRCA1 are presently unknown. We report the interaction of the BRCA1 BRCT domain with RAP80, a ubiquitin-binding protein. RAP80 targets a complex containing the BRCA1-BARD1 (BRCA1-associated ring domain protein 1) E3 ligase and the deubiquitinating enzyme (DUB) BRCC36 to MDC1-gammaH2AX-dependent lysine(6)- and lysine(63)-linked ubiquitin polymers at DSBs. These events are required for cell cycle checkpoint and repair responses to ionizing radiation, implicating ubiquitin chain recognition and turnover in the BRCA1-mediated repair of DSBs.
影响乳腺癌相关肿瘤抑制因子BRCA1的BRCT结构域的突变会破坏该蛋白与DNA双链断裂（DSB）的结合。目前尚不清楚BRCA1识别的DSB处的分子结构。我们报道了BRCA1的BRCT结构域与RAP80（一种泛素结合蛋白）的相互作用。RAP80将一个包含BRCA1 - BARD1（BRCA1相关环结构域蛋白1）E3连接酶和去泛素化酶（DUB）BRCC36的复合物靶向到DSB处依赖MDC1 - γH2AX的赖氨酸（6）-和赖氨酸（63）-连接的泛素聚合物上。这些事件是细胞周期检查点以及对电离辐射的修复反应所必需的，这表明泛素链识别和周转参与了BRCA1介导的DSB修复。
