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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...

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Autores principales: Santos-Pereira, José M., Herrero, Ana B., García-Rubio, María L., Marín, Antonio, Moreno, Sergio, Aguilera, Andrés
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2013
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.
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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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