G1期细胞对DNA双链断裂反应的差异调控
Differential regulation of the cellular response to DNA double-strand breaks in G1.
作者信息
Barlow Jacqueline H, Lisby Michael, Rothstein Rodney
机构信息
Department of Genetics and Development, Columbia University Medical Center, 701 West 168th Street, New York, NY 10032-2704, USA.
出版信息
Mol Cell. 2008 Apr 11;30(1):73-85. doi: 10.1016/j.molcel.2008.01.016.
Abstract
Double-strand breaks (DSBs) are potentially lethal DNA lesions that can be repaired by either homologous recombination (HR) or nonhomologous end-joining (NHEJ). We show that DSBs induced by ionizing radiation (IR) are efficiently processed for HR and bound by Rfa1 during G1, while endonuclease-induced breaks are recognized by Rfa1 only after the cell enters S phase. This difference is dependent on the DNA end-binding Yku70/Yku80 complex. Cell-cycle regulation is also observed in the DNA damage checkpoint response. Specifically, the 9-1-1 complex is required in G1 cells to recruit the Ddc2 checkpoint protein to damaged DNA, while, upon entry into S phase, the cyclin-dependent kinase Cdc28 and the 9-1-1 complex both serve to recruit Ddc2 to foci. Together, these results demonstrate that the DNA repair machinery distinguishes between different types of damage in G1, which translates into different modes of checkpoint activation in G1 and S/G2 cells.
摘要
双链断裂（DSB）是具有潜在致死性的DNA损伤，可通过同源重组（HR）或非同源末端连接（NHEJ）进行修复。我们发现，电离辐射（IR）诱导的DSB在G1期能被高效处理用于HR，并被Rfa1结合，而内切核酸酶诱导的断裂只有在细胞进入S期后才被Rfa1识别。这种差异依赖于DNA末端结合的Yku70/Yku80复合物。在DNA损伤检查点反应中也观察到了细胞周期调控。具体而言，G1期细胞需要9-1-1复合物将检查点蛋白Ddc2招募到受损DNA处，而进入S期后，细胞周期蛋白依赖性激酶Cdc28和9-1-1复合物都能将Ddc2招募到病灶处。这些结果共同表明，DNA修复机制在G1期能区分不同类型的损伤，这转化为G1期和S/G2期细胞中不同的检查点激活模式。
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