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

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 se...

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Autores principales: Domingo-Prim, Judit, Endara-Coll, Martin, Bonath, Franziska, Jimeno, Sonia, Prados-Carvajal, Rosario, Friedländer, Marc R., Huertas, Pablo, Visa, Neus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513946/
https://www.ncbi.nlm.nih.gov/pubmed/31086179
http://dx.doi.org/10.1038/s41467-019-10153-9
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author Domingo-Prim, Judit
Endara-Coll, Martin
Bonath, Franziska
Jimeno, Sonia
Prados-Carvajal, Rosario
Friedländer, Marc R.
Huertas, Pablo
Visa, Neus
author_facet Domingo-Prim, Judit
Endara-Coll, Martin
Bonath, Franziska
Jimeno, Sonia
Prados-Carvajal, Rosario
Friedländer, Marc R.
Huertas, Pablo
Visa, Neus
author_sort Domingo-Prim, Judit
collection PubMed
description 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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spelling pubmed-65139462019-05-15 EXOSC10 is required for RPA assembly and controlled DNA end resection at DNA double-strand breaks Domingo-Prim, Judit Endara-Coll, Martin Bonath, Franziska Jimeno, Sonia Prados-Carvajal, Rosario Friedländer, Marc R. Huertas, Pablo Visa, Neus Nat Commun Article 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. Nature Publishing Group UK 2019-05-13 /pmc/articles/PMC6513946/ /pubmed/31086179 http://dx.doi.org/10.1038/s41467-019-10153-9 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Domingo-Prim, Judit
Endara-Coll, Martin
Bonath, Franziska
Jimeno, Sonia
Prados-Carvajal, Rosario
Friedländer, Marc R.
Huertas, Pablo
Visa, Neus
EXOSC10 is required for RPA assembly and controlled DNA end resection at DNA double-strand breaks
title EXOSC10 is required for RPA assembly and controlled DNA end resection at DNA double-strand breaks
title_full EXOSC10 is required for RPA assembly and controlled DNA end resection at DNA double-strand breaks
title_fullStr EXOSC10 is required for RPA assembly and controlled DNA end resection at DNA double-strand breaks
title_full_unstemmed EXOSC10 is required for RPA assembly and controlled DNA end resection at DNA double-strand breaks
title_short EXOSC10 is required for RPA assembly and controlled DNA end resection at DNA double-strand breaks
title_sort exosc10 is required for rpa assembly and controlled dna end resection at dna double-strand breaks
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513946/
https://www.ncbi.nlm.nih.gov/pubmed/31086179
http://dx.doi.org/10.1038/s41467-019-10153-9
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