The DNA damage response mediator MDC1 directly interacts with the anaphase-promoting complex/cyclosome
The DNA damage response mediator MDC1 directly interacts with the anaphase-promoting complex/cyclosome
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DOI：
10.1074/jbc.m705890200
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发表时间：
2007-11-02
影响因子：
4.8
通讯作者：
Goldberg, Michal
中科院分区：
文献类型：
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作者：
Coster, Gideon;Hayouka, Zvi;Goldberg, Michal
MDC1(NFBD1)是细胞对DNA损伤反应的中介，在检验点激活和DNA修复中起着重要作用。在这里，我们确定了DNA损伤反应和细胞周期调节之间的相互作用。我们发现MDC1结合了后期促进复合体/环体(APC/C)，这是一种控制细胞周期的E3泛素连接酶。这种相互作用是直接的，由MDC1的串联BRCA1 C-末端结构域和APC/C亚基的CDc27(APC3)亚基的C末端介导。它需要CDc27的磷酸化，并在诱导DNA损伤后增强。我们发现MDC1的串联BRCA1 C-末端结构域直接与组蛋白H_2AX(Gamma-H_2AX)的磷酸化形式结合，也通过相同的机制与APC/C结合，因为与Gamma-H_2AX和CDC27的C末端相对应的磷酸肽相互竞争与MDC1的结合。我们的结果揭示了细胞对DNA损伤的反应和细胞周期调节之间的联系，表明MDC1在检查点调节中发挥作用，通过结合APC/C来执行这一作用的一部分。
MDC1 (NFBD1), a mediator of the cellular response to DNA damage, plays an important role in checkpoint activation and DNA repair. Here we identified a cross-talk between the DNA damage response and cell cycle regulation. We discovered that MDC1 binds the anaphase-promoting complex/cyclosome ( APC/C), an E3 ubiquitin ligase that controls the cell cycle. The interaction is direct and is mediated by the tandem BRCA1 C-terminal domains of MDC1 and the C terminus of the Cdc27 ( APC3) subunit of the APC/C. It requires the phosphorylation of Cdc27 and is enhanced after induction of DNA damage. We show that the tandem BRCA1 C-terminal domains of MDC1, known to directly bind the phosphorylated form of histone H2AX (gamma-H2AX), also bind the APC/C by the same mechanism, as phosphopeptides that correspond to the C termini of gamma-H2AX and Cdc27 competed with each other for the binding to MDC1. Our results reveal a link between the cellular response to DNA damage and cell cycle regulation, suggesting that MDC1, known to have a role in checkpoint regulation, executes part of this role by binding the APC/C.