Sumoylation of MDC1 is important for proper DNA damage response
Sumoylation of MDC1 is important for proper DNA damage response
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MDC1 的苏酰化对于正确的 DNA 损伤反应很重要
DOI：
10.1038/emboj.2012.158
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发表时间：
2012-06-29
期刊：
影响因子：
11.4
通讯作者：
Lou, Zhenkun
中科院分区：
文献类型：
--
作者：
Luo, Kuntian;Zhang, Haoxing;Lou, Zhenkun
许多DNA损伤因子，如MDC 1和53BP 1，在DNA损伤后重新分布到DNA损伤位点。然而，这些因子在DNA损伤位点的周转机制仍然是个谜。在这里，我们表明，MDC1是sumoylated DNA损伤后，和在Lys1840的sumoylation MDC1降解和MDC1和53BP1从DNA损伤的网站去除所需的MDC1。SUMO化的MDC1被SUMO靶向的E3泛素连接酶RNF4识别和泛素化。MDC1 Lys 1840（K1840R）突变导致CtIP、复制蛋白A和Rad51在DNA损伤位点的累积受损，并导致同源重组（HR）缺陷。MDC1K1840R突变引起的HR缺陷可通过下调53BP1来挽救。这些结果揭示了DNA损伤因子在DNA损伤位点的组装和分解的复杂动力学，以迅速响应DNA损伤。
In response to DNA damage, many DNA damage factors, such as MDC1 and 53BP1, redistribute to sites of DNA damage. The mechanism governing the turnover of these factors at DNA damage sites, however, remains enigmatic. Here, we show that MDC1 is sumoylated following DNA damage, and the sumoylation of MDC1 at Lys1840 is required for MDC1 degradation and removal of MDC1 and 53BP1 from sites of DNA damage. Sumoylated MDC1 is recognized and ubiquitinated by the SUMO‐targeted E3 ubiquitin ligase RNF4. Mutation of the MDC1 Lys 1840 (K1840R) results in impaired CtIP, replication protein A, and Rad51 accumulation at sites of DNA damage and defective homologous recombination (HR). The HR defect caused by MDC1K1840R mutation could be rescued by 53BP1 downregulation. These results reveal the intricate dynamics governing the assembly and disassembly of DNA damage factors at sites of DNA damage for prompt response to DNA damage.