Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage

被引:346
作者
Bin Wang [1 ]
Elledge, Stephen J. [1 ]
机构
[1] Harvard Univ, Sch Med, Howard Hughes Med Inst, Dept Genet,Ctr Genet & Genom, Boston, MA 02115 USA
关键词
breast cancer; ubiquitination; Mdc1; 53BP1; K63;
D O I
10.1073/pnas.0710061104
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The Brca1 A complex contains Brca1/Bard1, Abraxas, Rap80, and Brcc36; however, with the exception of the Brca1-Abraxas interaction, how the A complex is assembled is not known. The A complex is localized to sites of DNA damage through the UIM domains of RAP80, which bind K63-linked polyubiquitin chains. In this study, we identified an FHA domain RING finger E3 ubiquitin ligase, RNF8, and an E2-conjugating enzyme known to form K63-polyubiquitin chains, Ubc13, each of which is required to recruit the Brca1 A complex to sites of DNA damage. Rnf8 localizes to sites of DNA damage through an FHA-domain-containing region. We found that Rap80 contains an Abraxas interaction domain [AIR (Abraxas-interacting region)] required for association of Rap80 with Abraxas, Brca1, and Brcc36. Abraxas and Brcc36 associate through coiled-coil domains on each protein. These data suggest a model through which Ubc13 and Rnf8 are recruited to sites of DNA damage through DNA-damage-induced phosphorylation of a chromatin-associated protein and generate polyubiquitin chains that then recruit Rap80 and the entire Brca1 A complex to DNA-damage foci. This sequential E3 ubiquitin ligase recruitment constitutes a ubiquitin ligase cascade required for DNA repair and checkpoint signaling.
引用
收藏
页码:20759 / 20763
页数:5
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