EXOSC10 is required for RPA assembly and controlled DNA end resection at DNA double-strand breaks

Judit Domingo-Prim, Martin Endara-Coll, Franziska Bonath, Sonia Jimeno, Rosario Prados-Carvajal, Marc R. Friedländer, Pablo Huertas and Neus Visa ()
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Judit Domingo-Prim: The Wenner-Gren Institute, Stockholm University
Martin Endara-Coll: The Wenner-Gren Institute, Stockholm University
Franziska Bonath: The Wenner-Gren Institute, Stockholm University
Sonia Jimeno: Universidad de Sevilla-CSIC-Universidad Pablo de Olavide
Rosario Prados-Carvajal: Universidad de Sevilla-CSIC-Universidad Pablo de Olavide
Marc R. Friedländer: The Wenner-Gren Institute, Stockholm University
Pablo Huertas: Universidad de Sevilla-CSIC-Universidad Pablo de Olavide
Neus Visa: The Wenner-Gren Institute, Stockholm University

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-10153-9

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