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RNA transcripts stimulate homologous recombination by forming DR-loops

机译：RNA转录物通过形成DR循环刺激同源重组

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摘要

Homologous recombination (HR) repairs DNA double-strand breaks (DSBs) in the S and G2 phases of the cell cycle~(1-3). Several HR proteins are preferentially recruited to DSBs at transcriptionally active loci~(4-10), but how transcription promotes HR is poorly understood. Here we develop an assay to assess the effect of local transcription on HR. Using this assay, we find that transcription stimulates HR to a substantial extent. Tethering RNA transcripts to the vicinity of DSBs recapitulates the effects of local transcription, which suggests that transcription enhances HR through RNA transcripts. Tethered RNA transcripts stimulate HR in a sequence- and orientation-dependent manner, indicating that they function by forming DNA-RNA hybrids. In contrast to most HR proteins, RAD51-associated protein 1 (RAD51AP1) only promotes HR when local transcription is active. RAD51AP1 drives the formation of R-loops in vitro and is required for tethered RNAs to stimulate HR in cells. Notably, RAD51AP1 is necessary for the DSB-induced formation of DNA-RNA hybrids in donor DNA, linking R-loops to D-loops. In vitro, RAD51AP1-generated R-loops enhance the RAD51-mediated formation of D-loops locally and give rise to intermediates that we term 'DR-loops', which contain both DNA-DNA and DNA-RNA hybrids and favour RAD51 function. Thus, at DSBs in transcribed regions, RAD51AP1 promotes the invasion of RNA transcripts into donor DNA, and stimulates HR through the formation of DR-loops.
机译：同源重组（HR）的修理的DNA细胞周期〜（1-3）的在S双链断裂（DSB的）和G2期。一些HR蛋白优先招募到DNA双链断裂的转录活性位点〜（4-10），但转录如何促进人力资源知之甚少。在这里，我们开发了检测，以评估当地的转录对人力资源的影响。使用这种方法，我们发现，转录能刺激HR在很大程度上。圈养RNA转录到DNA双链断裂附近概括当地的转录，这表明通过RNA转录转录增强人力资源的作用。拴系的RNA转录刺激以序列和取向依赖性HR，这表明它们通过形成DNA-RNA杂交起作用。与大多数HR蛋白，RAD51相关蛋白1（RAD51AP1）仅促进HR当本地转录激活。 RAD51AP1驱动体外R-环路的形成和所需的系链的RNA，以刺激在HR细胞。值得注意的是，RAD51AP1是必要的DNA-RNA杂交在供体DNA中的DSB诱导的形成，连接R-循环到d-环路。在体外，RAD51AP1生成的R-环路增强d-环的RAD51介导的形成本地和产生的中间体，我们术语“DR-环”，它同时包含DNA-DNA和DNA-RNA杂交和青睐RAD51功能。因此，在转录区的DNA双链断裂，RAD51AP1促进RNA转录物通过DR-环路的形成侵入供体DNA，并刺激HR。

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  • 来源
    《Nature》 |2021年第7862期|283-288|共6页
  • 作者

    Jian Ouyang; Tribhuwan Yadav; Jia-Min Zhang; Haibo Yang; Esther Rheinbay; Hongshan Guo; Daniel A Haber; Li Lan; Lee Zou;

  • 作者单位

    Massachusetts General Hospital Cancer Center Harvard Medical School;

    Massachusetts General Hospital Cancer Center Harvard Medical School;

    Massachusetts General Hospital Cancer Center Harvard Medical School;

    Massachusetts General Hospital Cancer Center Harvard Medical School|Department of Radiation Oncology Massachusetts General Hospital Harvard Medical School;

    Massachusetts General Hospital Cancer Center Harvard Medical School;

    Massachusetts General Hospital Cancer Center Harvard Medical School|Howard Hughes Medical Institute Massachusetts General Hospital;

    Massachusetts General Hospital Cancer Center Harvard Medical School|Howard Hughes Medical Institute Massachusetts General Hospital;

    Massachusetts General Hospital Cancer Center Harvard Medical School|Department of Radiation Oncology Massachusetts General Hospital Harvard Medical School;

    Massachusetts General Hospital Cancer Center Harvard Medical School|Department of Pathology Massachusetts General Hospital Harvard Medical School;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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