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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Launching a ubiquitination cascade at DNA breaks
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Launching a ubiquitination cascade at DNA breaks

机译：在DNA断裂时启动泛素级联反应

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The BRCA1 gene was cloned in 1994 as the first tumor suppressor of hereditary breast cancer, and it has been heavily studied ever since. The Brcal protein is multifunctional and critical for the maintenance of genomic stability. Among its many roles, Brcal is part of an E3 ubiquitin ligase important for homologous recombination (HR) and signaling of double-strand DNA breaks (DSBs). In response to DSBs, the checkpoint kinases ATM and ATR phos-phorylate the histone variant H2AX adjacent to the breaks, which then recruits the mediator protein Mdcl and other DNA repair and damage signaling proteins, including Brcal. Once recruited to DSBs, Brcal colocalizes with these repair and signaling proteins in discrete nuclear foci. Both H2AX and Mdcl are required for the formation of Brcal foci, but how they contribute to Brcal recruitment has not been clear. Part of this "missing link" was recently revealed. Rap80, a Brcal-associating protein, targets Brcal to DSBs through its UIM domains, which recognize polyubiquitin chains (1-3). In this issue of PNAS, Wang and Elledge (4) present the discovery of Rnf8 as an E3 ubiquitin ligase that recognizes phosphor-ylated proteins at DSBs and generates the polyubiquitin chains recognized by Rap80, thereby connecting the phosphorylation-and ubiquitination-regulated steps during the recruitment of Brcal.
机译：BRCA1基因于1994年被克隆为遗传性乳腺癌的第一个肿瘤抑制因子，此后一直受到广泛研究。 Brcal蛋白具有多功能性，对于维持基因组稳定性至关重要。在众多角色中，Brcal是E3泛素连接酶的一部分，对同源重组（HR）和双链DNA断裂（DSBs）信号传导很重要。响应DSB，检查点激酶ATM和ATR磷酸化断裂附近的组蛋白变体H2AX，然后募集介体蛋白Mdcl和其他DNA修复和破坏信号蛋白，包括Brcal。一旦被招募到DSB，Brcal就会与这些修复蛋白和信号蛋白共定位于离散的核病灶中。 H2AX和Mdcl都是形成Brcal灶所必需的，但是它们如何促进Brcal募集尚不清楚。该“缺失链接”的一部分最近被发现。 Rap80是Brcal的相关蛋白，通过其UIM域将Brcal靶向DSB，该UIM域识别多泛素链（1-3）。在本期PNAS中，Wang和Elledge（4）提出了Rnf8作为E3泛素连接酶的发现，该酶识别DSB处的磷酸化蛋白并生成Rap80识别的多聚泛素链，从而将磷酸化和泛素化调控的步骤连接在一起。 Brcal的招募。

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