染色质相关蛋白MDC1和53BP1在哺乳动物双链断裂修复中的不同作用。
Distinct roles of chromatin-associated proteins MDC1 and 53BP1 in mammalian double-strand break repair.
作者信息
Xie Anyong, Hartlerode Andrea, Stucki Manuel, Odate Shobu, Puget Nadine, Kwok Amy, Nagaraju Ganesh, Yan Catherine, Alt Frederick W, Chen Junjie, Jackson Stephen P, Scully Ralph
机构信息
Department of Medicine, Harvard Medical School and Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA.
出版信息
Mol Cell. 2007 Dec 28;28(6):1045-57. doi: 10.1016/j.molcel.2007.12.005.
Phosphorylated histone H2AX ("gamma-H2AX") recruits MDC1, 53BP1, and BRCA1 to chromatin near a double-strand break (DSB) and facilitates efficient repair of the break. It is unclear to what extent gamma-H2AX-associated proteins act in concert and to what extent their functions within gamma-H2AX chromatin are distinct. We addressed this question by comparing the mechanisms of action of MDC1 and 53BP1 in DSB repair (DSBR). We find that MDC1 functions primarily in homologous recombination/sister chromatid recombination, in a manner strictly dependent upon its ability to interact with gamma-H2AX but, unexpectedly, not requiring recruitment of 53BP1 or BRCA1 to gamma-H2AX chromatin. In contrast, 53BP1 functions in XRCC4-dependent nonhomologous end-joining, likely mediated by its interaction with dimethylated lysine 20 of histone H4 but, surprisingly, independent of H2AX. These results suggest a specialized adaptation of the "histone code" in which distinct histone tail-protein interactions promote engagement of distinct DSBR pathways.
磷酸化组蛋白H2AX（“γ-H2AX”）将MDC1、53BP1和BRCA1募集到双链断裂（DSB）附近的染色质上，并促进断裂的有效修复。目前尚不清楚γ-H2AX相关蛋白在多大程度上协同作用，以及它们在γ-H2AX染色质中的功能在多大程度上是不同的。我们通过比较MDC1和53BP1在DSB修复（DSBR）中的作用机制来解决这个问题。我们发现，MDC1主要在同源重组/姐妹染色单体重组中发挥作用，其方式严格依赖于其与γ-H2AX相互作用的能力，但出乎意料的是，不需要将53BP1或BRCA1募集到γ-H2AX染色质上。相比之下，53BP1在依赖XRCC4的非同源末端连接中发挥作用，可能是由其与组蛋白H4的二甲基化赖氨酸20的相互作用介导的，但令人惊讶的是，它不依赖于H2AX。这些结果表明了“组蛋白密码”的一种特殊适应性，其中不同的组蛋白尾巴-蛋白质相互作用促进了不同DSBR途径的参与。
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