期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-10153-9
关键词
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资金
- Swedish Research Council [2015-04553, 1403003]
- Swedish Cancer Society [CAN 2016/460]
- Spanish Ministry of Economy and Competitivity [SAF2016-74855-P]
- Department of Molecular Biosciences, the Wenner-Gren Institute at Stockholm University
- short-term EMBO fellowships [STF-7513-2018, STF-7764-2018]
- SFO from the Faculty of Science at the Stockholm University
- Vinnova [2015-04553] Funding Source: Vinnova
- Swedish Research Council [2015-04553] Funding Source: Swedish Research Council
The exosome is a ribonucleolytic complex that plays important roles in RNA metabolism. Here we show that the exosome is necessary for the repair of DNA double-strand breaks (DSBs) in human cells and that RNA clearance is an essential step in homologous recombination. Transcription of DSB-flanking sequences results in the production of damage-induced long non-coding RNAs (dilncRNAs) that engage in DNA-RNA hybrid formation. Depletion of EXOSC10, an exosome catalytic subunit, leads to increased dilncRNA and DNA-RNA hybrid levels. Moreover, the targeting of the ssDNA-binding protein RPA to sites of DNA damage is impaired whereas DNA end resection is hyper-stimulated in EXOSC10-depleted cells. The DNA end resection deregulation is abolished by transcription inhibitors, and RNase H1 overexpression restores the RPA recruitment defect caused by EXOSC10 depletion, which suggests that RNA clearance of newly synthesized dilncRNAs is required for RPA recruitment, controlled DNA end resection and assembly of the homologous recombination machinery.
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