Feedback-regulated poly(ADP-ribosyl)ation by PARP-1 is required for rapid response to DNA damage in living cells.
Feedback-regulated poly(ADP-ribosyl)ation by PARP-1 is required for rapid response to DNA damage in living cells.
复制标题
通过PARP-1，需要通过PARP-1进行反馈调节的聚（ADP-核糖基），才能快速响应活细胞中的DNA损伤。
DOI：
10.1093/nar/gkm933
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发表时间：
2007
影响因子：
14.9
通讯作者：
Leonhardt, Heinrich
中科院分区：
文献类型：
--
作者：
Mortusewicz, Oliver;Ame, Jean-Christophe;Schreiber, Valerie;Leonhardt, Heinrich
基因组完整性不断受到多种外源性和内源性 DNA 损伤的威胁。生存取决于对这些病变的立即识别和修复因子的快速募集。使用激光微辐射和活细胞显微镜，我们发现 DNA 损伤依赖性聚（ADP-核糖）聚合酶（PARP）PARP-1 和 PARP-2 被招募到 DNA 损伤位点，但具有不同的动力学和作用。通过特定的 PARP 抑制剂和突变，我们可以证明 PARP-1 的初始募集是由 DNA 结合域介导的。然后，PARP-1 激活和局部聚（ADP-核糖）合成生成结合位点，用于第二波 PARP-1 募集以及加载平台 XRCC1 在修复位点的快速积累。进一步的 PARP-1 聚（ADP-核糖基）化最终引发 PARP-1 的释放。我们得出的结论是，反馈调节的 PARP-1 募集以及 DNA 损伤处伴随的局部聚（ADP-核糖基）化放大了修复因子快速募集的信号，从而能够有效恢复基因组完整性。
Genome integrity is constantly threatened by DNA lesions arising from numerous exogenous and endogenous sources. Survival depends on immediate recognition of these lesions and rapid recruitment of repair factors. Using laser microirradiation and live cell microscopy we found that the DNA-damage dependent poly(ADP-ribose) polymerases (PARP) PARP-1 and PARP-2 are recruited to DNA damage sites, however, with different kinetics and roles. With specific PARP inhibitors and mutations, we could show that the initial recruitment of PARP-1 is mediated by the DNA-binding domain. PARP-1 activation and localized poly(ADP-ribose) synthesis then generates binding sites for a second wave of PARP-1 recruitment and for the rapid accumulation of the loading platform XRCC1 at repair sites. Further PARP-1 poly(ADP-ribosyl)ation eventually initiates the release of PARP-1. We conclude that feedback regulated recruitment of PARP-1 and concomitant local poly(ADP-ribosyl)ation at DNA lesions amplifies a signal for rapid recruitment of repair factors enabling efficient restoration of genome integrity.