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EXOSC10 is required for RPA assembly and controlled DNA end resection at DNA double-strand breaks
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
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Number of Authors: 82019 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 2135Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2019. Vol. 10, article id 2135
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Biological Sciences
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URN: urn:nbn:se:su:diva-169245DOI: 10.1038/s41467-019-10153-9ISI: 000467703400003PubMedID: 31086179OAI: oai:DiVA.org:su-169245DiVA, id: diva2:1323768
Available from: 2019-06-12 Created: 2019-06-12 Last updated: 2019-06-12Bibliographically approved

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Domingo-Prim, JuditEndara-Coll, MartinBonath, FranziskaFriedländer, Marc R.Visa, Neus
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Department of Molecular Biosciences, The Wenner-Gren InstituteScience for Life Laboratory (SciLifeLab)
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