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: Santos Pereira, José María, Herrero, Ana B., García Rubio, María Luisa, Marín Rodríguez, Antonio, Moreno, Sergio, Aguilera López, Andrés
Tipo de recurso: artículo
Fecha de publicación:2013
País:España
Institución:Universidad de Sevilla (US)
Repositorio:idUS. Depósito de Investigación de la Universidad de Sevilla
OAI Identifier:oai:idus.us.es:11441/29092
Acceso en línea:http://hdl.handle.net/11441/29092
https://doi.org/10.1101/gad.229880.113
Access Level:acceso abierto
Palabra clave:R loops
transcription-associated genome instability
transcription–replication conflicts
Npl3
hnRNPs
DNA damage response
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spelling The Npl3 hnRNP prevents R-loop-mediated transcription–replication conflicts and genome instabilitySantos Pereira, José MaríaHerrero, Ana B.García Rubio, María LuisaMarín Rodríguez, AntonioMoreno, SergioAguilera López, AndrésR loopstranscription-associated genome instabilitytranscription–replication conflictsNpl3hnRNPsDNA damage responseTranscription 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 PressGenética2013info:eu-repo/semantics/articleapplication/pdfapplication/pdfhttp://hdl.handle.net/11441/29092https://doi.org/10.1101/gad.229880.113reponame:idUS. Depósito de Investigación de la Universidad de Sevillainstname:Universidad de Sevilla (US)InglésGenes & development, 27(22), 2445-2458http://dx.doi.org/10.1101/gad.229880.113info:eu-repo/semantics/openAccessoai:idus.us.es:11441/290922026-06-17T12:51:07Z
dc.title.none.fl_str_mv 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
spellingShingle The Npl3 hnRNP prevents R-loop-mediated transcription–replication conflicts and genome instability
Santos Pereira, José María
R loops
transcription-associated genome instability
transcription–replication conflicts
Npl3
hnRNPs
DNA damage response
title_short 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_sort The Npl3 hnRNP prevents R-loop-mediated transcription–replication conflicts and genome instability
dc.creator.none.fl_str_mv Santos Pereira, José María
Herrero, Ana B.
García Rubio, María Luisa
Marín Rodríguez, Antonio
Moreno, Sergio
Aguilera López, Andrés
author Santos Pereira, José María
author_facet Santos Pereira, José María
Herrero, Ana B.
García Rubio, María Luisa
Marín Rodríguez, Antonio
Moreno, Sergio
Aguilera López, Andrés
author_role author
author2 Herrero, Ana B.
García Rubio, María Luisa
Marín Rodríguez, Antonio
Moreno, Sergio
Aguilera López, Andrés
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Genética
dc.subject.none.fl_str_mv R loops
transcription-associated genome instability
transcription–replication conflicts
Npl3
hnRNPs
DNA damage response
topic R loops
transcription-associated genome instability
transcription–replication conflicts
Npl3
hnRNPs
DNA damage response
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.
publishDate 2013
dc.date.none.fl_str_mv 2013
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/11441/29092
https://doi.org/10.1101/gad.229880.113
url http://hdl.handle.net/11441/29092
https://doi.org/10.1101/gad.229880.113
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Genes & development, 27(22), 2445-2458
http://dx.doi.org/10.1101/gad.229880.113
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Cold Spring Harbor Laboratory Press
publisher.none.fl_str_mv Cold Spring Harbor Laboratory Press
dc.source.none.fl_str_mv reponame:idUS. Depósito de Investigación de la Universidad de Sevilla
instname:Universidad de Sevilla (US)
instname_str Universidad de Sevilla (US)
reponame_str idUS. Depósito de Investigación de la Universidad de Sevilla
collection idUS. Depósito de Investigación de la Universidad de Sevilla
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300724

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