MDC1通过将NBS1靶向DNA双链断裂来调节S期内检查点。
MDC1 regulates intra-S-phase checkpoint by targeting NBS1 to DNA double-strand breaks.
作者信息
Wu Liming, Luo Kuntian, Lou Zhenkun, Chen Junjie
机构信息
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
出版信息
Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11200-5. doi: 10.1073/pnas.0802885105. Epub 2008 Aug 4.
The product of the Nijmegen breakage syndrome gene (NBS1) plays crucial roles in DNA damage response through its association with many proteins, including MRE11 and RAD50. However, it remains to be determined exactly how NBS1 accumulates at or near DNA double-strand breaks. Here we report that MDC1 directly binds to NBS1 and targets NBS1 to the sites of DNA damage. The MDC1-NBS1 interaction occurs through a specific region (residues 200-420) of MDC1, which contains multiple consensus casein kinase 2 (CK2) phosphorylation sites. In addition, this interaction requires both the forkhead-associated (FHA) and tandem BRCA1 C-terminal (BRCT) domains of NBS1. Disruption of the MDC1-NBS1 interaction results in failure of NBS1 accumulation at DNA double-strand breaks and impairment of intra-S checkpoint activation. These studies provide important mechanistic insights as to how MDC1 regulates NBS1 and the intra-S-phase checkpoint in response to DNA damage.
奈梅亨断裂综合征基因（NBS1）的产物通过与包括MRE11和RAD50在内的多种蛋白质结合，在DNA损伤反应中发挥关键作用。然而，NBS1究竟如何在DNA双链断裂处或其附近积累仍有待确定。在此，我们报告MDC1直接与NBS1结合，并将NBS1靶向到DNA损伤位点。MDC1与NBS1的相互作用通过MDC1的一个特定区域（第200 - 420位氨基酸残基）发生，该区域包含多个共有酪蛋白激酶2（CK2）磷酸化位点。此外，这种相互作用需要NBS1的叉头相关（FHA）结构域和串联BRCA1 C末端（BRCT）结构域。MDC1与NBS1相互作用的破坏导致NBS1无法在DNA双链断裂处积累，并损害S期内检查点的激活。这些研究为MDC1如何响应DNA损伤调节NBS1和S期内检查点提供了重要的机制见解。
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