CtIP蛋白的翻译后修饰在DNA损伤修复中的功能及作用机制研究

DNA双链断裂(double-strand breaks,DSBs)的末端切割(DNA end resection)是同源重组(homologous recombination,HR)修复的关键步骤。然而，细胞中DSBs末端切割的程度是如何被精确调控的还很不清楚。最近我们发现DSBs能够诱导末端切割的关键因子CtIP在K578位点的SUMO化修饰。进一步研究还发现CtIP蛋白在该位点的SUMO化修饰依赖于ATM介导的CtIP蛋白的磷酸化修饰。有趣的是，抑制CtIP蛋白的SUMO化修饰会导致过量的CtIP蛋白在DSBs位点的聚集以及过度的DSBs末端切割。通过该项目的实施，我们不仅可以阐明CtIP如何通过不同的蛋白质翻译后修饰调控DSBs末端切割的程度，还可以进一步揭示精确的DSBs末端切割调控在维持基因组稳定性过程中的重要作用，并将为HR相关疾病的治疗提供新的分子靶标及理论支持。

DNA-end resection is a critical step in the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR). However, the mechanisms governing the extent of resection at DSB sites undergoing homology-directed repair remain enigmatic. Here we show that, upon DNA damage, the key resection factor CtIP is modified by the ubiquitin-like protein SUMO at lysine residue 578. SUMOylation of CtIP occurs on chromatin and requires its prior hyperphosphorylation by the ATM protein kinase. Deregulation of CtIP SUMOylation causes aberrant accumulation of CtIP at DSB sites, which in turn results in uncontrolled excessive resection. These findings reveal a previously unidentified regulatory mechanism that regulates the CtIP activity at DSB sites and hence the extent of end resection via ATM-dependent differential posttranslational modifications of CtIP.