CDK 靶向 NBS1 促进 DNA 末端切除、复制起始和同源重组。
CDK targeting of NBS1 promotes DNA-end resection, replication restart and homologous recombination.
机构信息
Department of Biochemistry, Wellcome Trust and Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK.
出版信息
EMBO Rep. 2012 Jun;13(6):561-8. doi: 10.1038/embor.2012.58.
Abstract
The conserved MRE11–RAD50–NBS1 (MRN) complex is an important sensor of DNA double-strand breaks (DSBs) and facilitates DNA repair by homologous recombination (HR) and end joining. Here, we identify NBS1 as a target of cyclin-dependent kinase (CDK) phosphorylation. We show that NBS1 serine 432 phosphorylation occurs in the S, G2 and M phases of the cell cycle and requires CDK activity. This modification stimulates MRN-dependent conversion of DSBs into structures that are substrates for repair by HR. Impairment of NBS1 phosphorylation not only negatively affects DSB repair by HR, but also prevents resumption of DNA replication after replication-fork stalling. Thus, CDK-mediated NBS1 phosphorylation defines a molecular switch that controls the choice of repair mode for DSBs.
摘要
MRE11-RAD50-NBS1 (MRN) 复合物是一种重要的 DNA 双链断裂 (DSB) 传感器，通过同源重组 (HR) 和末端连接促进 DNA 修复。在这里，我们确定 NBS1 是细胞周期蛋白依赖性激酶 (CDK) 磷酸化的靶标。我们表明，NBS1 丝氨酸 432 磷酸化发生在细胞周期的 S、G2 和 M 期，需要 CDK 活性。这种修饰刺激了 MRN 依赖性将 DSB 转化为 HR 修复的底物的结构。NBS1 磷酸化的损伤不仅会对 HR 介导的 DSB 修复产生负面影响，还会阻止复制叉停滞后 DNA 复制的恢复。因此，CDK 介导的 NBS1 磷酸化定义了一个分子开关，控制 DSB 修复模式的选择。
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