Cell Res:戚益军等小非编码RNA参与DNA损伤修复机制研究获进展



2014年3月,中国科学院北京基因组研究所基因组变异与精准生物医学实验室杨运桂研究组与清华大学生命科学学院戚益军研究组合作研究发现,小非编码RNA(diRNA)及其效应蛋白Ago2调控DNA同源重组修复重要因子Rad51在DNA双链断裂(double strand break, DSB)位点的招募,从而调节DNA修复的作用机制,相关论文在Cell Research在线发表。

DSB是真核生物基因组后果最严重的损伤,可以导致基因突变、基因组不稳定和细胞死亡,因此与包括癌症在内的多种疾病的发生密切相关。真核细胞已演化出了复杂的DSB修复机制,涉及到一系列感应蛋白、传导蛋白和效应蛋白的协调作用。在该合作团队此前的研究中(Cell ,2012),戚益军研究组首次发现了植物细胞中存在一类特异性受DSB诱导并在DSB修复中起到重要作用的小RNA,diRNA (DSB-induced small RNA),随后杨运桂研究组在哺乳动物细胞中确认这类特异性diRNA的存在。diRNA如何介导DSB修复尚不清楚。

科研人员利用生化和细胞生物学等手段,发现diRNA只调控DSB的同源重组(Homologous recombination)修复途径,而不影响非同源末端连接(Non-homologous end-joining)修复途径。这种特异性修复活性依赖于diRNA的效应蛋白Ago2。研究人员发现,Ago2可与同源重组修复重要因子Rad51形成复合物,并且Rad51在DSB位点的招募和同源重组修复活性取决于Ago2的催化活性及其结合小RNA的能力。DSB末端的加工,RPA和Mre11在单链DNA末端的装载不受diRNA和Ago2调控,说明Ago2很可能通过直接调节Rad51的招募发挥作用。这些研究结果表明,Ago2可能在diRNA的指导下,促进Rad51在DNA双链断裂位点的招募或滞留,从而调控同源重组活性,高效修复DNA损伤。

该研究进一步揭示了小RNA在DNA双链断裂修复过程中的保守性和重要功能,为后续从小RNA和DNA修复角度开展对人类疾病如恶性肿瘤发生发展研究提供了新思路。

该研究得到了中国科学院、科技部和国家自然科学基金委的资助。 (生物谷Bioon.com)

Cell Res:戚益军等小非编码RNA参与DNA损伤修复机制研究获进展

生物谷推荐的英文摘要:

Cell Research     doi: 10.1038/cr.2014.36

Ago2 facilitates Rad51 recruitment and DNA double-strand break repair by homologous recombination

Min Gao1,4, Wei Wei2,3, Ming-Ming Li1,4, Yong-Sheng Wu1, Zhaoqing Ba2,3, Kang-Xuan Jin1,4, Miao-Miao Li1,4, You-Qi Liao1,4, Samir Adhikari1,4, Zechen Chong1, Ting Zhang1, Cai-Xia Guo1, Tie-shan Tang5, Bing-Tao Zhu6, Xing-Zhi Xu6, Niels Mailand7, Yun-Gui Yang1,4, Yijun Qi2,3 and Jannie M Rendtlew Danielsen1,7

DNA double-strand breaks (DSBs) are highly cytotoxic lesions and pose a major threat to genome stability if not properly repaired. We and others have previously shown that a class of DSB-induced small RNAs (diRNAs) is produced from sequences around DSB sites. DiRNAs are associated with Argonaute (Ago) proteins and play an important role in DSB repair, though the mechanism through which they act remains unclear. Here, we report that the role of diRNAs in DSB repair is restricted to repair by homologous recombination (HR) and that it specifically relies on the effector protein Ago2 in mammalian cells. Interestingly, we show that Ago2 forms a complex with Rad51 and that the interaction is enhanced in cells treated with ionizing radiation. We demonstrate that Rad51 accumulation at DSB sites and HR repair depend on catalytic activity and small RNA-binding capability of Ago2. In contrast, DSB resection as well as RPA and Mre11 loading is unaffected by Ago2 or Dicer depletion, suggesting that Ago2 very likely functions directly in mediating Rad51 accumulation at DSBs. Taken together, our findings suggest that guided by diRNAs, Ago2 can promote Rad51 recruitment and/or retention at DSBs to facilitate repair by HR.




上一篇:【一城一忆致匠心】长株潭龚明科:我在口味王
下一篇:我国是对转基因产品标识最多的国家5类17种须强