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The Npl3 hnRNP prevents R-loop-mediated transcription–replication conflicts and genome instability
Transcription is a major obstacle for replication fork (RF) progression and a cause of genome instability. Part of this instability is mediated by cotranscriptional R loops, which are believed to increase by suboptimal assembly of the nascent messenger ribonucleoprotein particle (mRNP). However, no...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3841734/ https://www.ncbi.nlm.nih.gov/pubmed/24240235 http://dx.doi.org/10.1101/gad.229880.113 |
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author | Santos-Pereira, José M. Herrero, Ana B. García-Rubio, María L. Marín, Antonio Moreno, Sergio Aguilera, Andrés |
author_facet | Santos-Pereira, José M. Herrero, Ana B. García-Rubio, María L. Marín, Antonio Moreno, Sergio Aguilera, Andrés |
author_sort | Santos-Pereira, José M. |
collection | PubMed |
description | Transcription is a major obstacle for replication fork (RF) progression and a cause of genome instability. Part of this instability is mediated by cotranscriptional R loops, which are believed to increase by suboptimal assembly of the nascent messenger ribonucleoprotein particle (mRNP). However, no clear evidence exists that heterogeneous nuclear RNPs (hnRNPs), the basic mRNP components, prevent R-loop stabilization. Here we show that yeast Npl3, the most abundant RNA-binding hnRNP, prevents R-loop-mediated genome instability. npl3Δ cells show transcription-dependent and R-loop-dependent hyperrecombination and genome-wide replication obstacles as determined by accumulation of the Rrm3 helicase. Such obstacles preferentially occur at long and highly expressed genes, to which Npl3 is preferentially bound in wild-type cells, and are reduced by RNase H1 overexpression. The resulting replication stress confers hypersensitivity to double-strand break-inducing agents. Therefore, our work demonstrates that mRNP factors are critical for genome integrity and opens the option of using them as therapeutic targets in anti-cancer treatment. |
format | Online Article Text |
id | pubmed-3841734 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-38417342014-05-15 The Npl3 hnRNP prevents R-loop-mediated transcription–replication conflicts and genome instability Santos-Pereira, José M. Herrero, Ana B. García-Rubio, María L. Marín, Antonio Moreno, Sergio Aguilera, Andrés Genes Dev Research Paper Transcription is a major obstacle for replication fork (RF) progression and a cause of genome instability. Part of this instability is mediated by cotranscriptional R loops, which are believed to increase by suboptimal assembly of the nascent messenger ribonucleoprotein particle (mRNP). However, no clear evidence exists that heterogeneous nuclear RNPs (hnRNPs), the basic mRNP components, prevent R-loop stabilization. Here we show that yeast Npl3, the most abundant RNA-binding hnRNP, prevents R-loop-mediated genome instability. npl3Δ cells show transcription-dependent and R-loop-dependent hyperrecombination and genome-wide replication obstacles as determined by accumulation of the Rrm3 helicase. Such obstacles preferentially occur at long and highly expressed genes, to which Npl3 is preferentially bound in wild-type cells, and are reduced by RNase H1 overexpression. The resulting replication stress confers hypersensitivity to double-strand break-inducing agents. Therefore, our work demonstrates that mRNP factors are critical for genome integrity and opens the option of using them as therapeutic targets in anti-cancer treatment. Cold Spring Harbor Laboratory Press 2013-11-15 /pmc/articles/PMC3841734/ /pubmed/24240235 http://dx.doi.org/10.1101/gad.229880.113 Text en © 2013 Santos-Pereira et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/3.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/. |
spellingShingle | Research Paper Santos-Pereira, José M. Herrero, Ana B. García-Rubio, María L. Marín, Antonio Moreno, Sergio Aguilera, Andrés The Npl3 hnRNP prevents R-loop-mediated transcription–replication conflicts and genome instability |
title | The Npl3 hnRNP prevents R-loop-mediated transcription–replication conflicts and genome instability |
title_full | The Npl3 hnRNP prevents R-loop-mediated transcription–replication conflicts and genome instability |
title_fullStr | The Npl3 hnRNP prevents R-loop-mediated transcription–replication conflicts and genome instability |
title_full_unstemmed | The Npl3 hnRNP prevents R-loop-mediated transcription–replication conflicts and genome instability |
title_short | The Npl3 hnRNP prevents R-loop-mediated transcription–replication conflicts and genome instability |
title_sort | npl3 hnrnp prevents r-loop-mediated transcription–replication conflicts and genome instability |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3841734/ https://www.ncbi.nlm.nih.gov/pubmed/24240235 http://dx.doi.org/10.1101/gad.229880.113 |
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