The molecular chaperone ALYREF promotes R-loop resolution and maintains genome stability

Unscheduled R-loops usually cause DNA damage and replication stress, and are therefore a major threat to genome stability. Several RNA processing factors, including the conserved THO complex and its associated RNA and DNA-RNA helicase UAP56, prevent R-loop accumulation in cells. Here, we investigate...

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Detalles Bibliográficos
Autores: Bhandari, Jay, Guillén-Mendoza, Cristina, Banks, Kathryn, Eliaz, Lillian, Southwell, Sierra, Eyaa, Darriel, Luna, Rosa, Aguilera, Andrés, Xue, Xiaoyu
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/378587
Acceso en línea:http://hdl.handle.net/10261/378587
https://api.elsevier.com/content/abstract/scopus_id/85211055351
Access Level:acceso abierto
Palabra clave:ALYREF
DNA-RNA helicase
R-loop
TREX complex
UAP56
Genome instability
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spelling The molecular chaperone ALYREF promotes R-loop resolution and maintains genome stabilityBhandari, JayGuillén-Mendoza, CristinaBanks, KathrynEliaz, LillianSouthwell, SierraEyaa, DarrielLuna, RosaAguilera, AndrésXue, XiaoyuALYREFDNA-RNA helicaseR-loopTREX complexUAP56Genome instabilityUnscheduled R-loops usually cause DNA damage and replication stress, and are therefore a major threat to genome stability. Several RNA processing factors, including the conserved THO complex and its associated RNA and DNA-RNA helicase UAP56, prevent R-loop accumulation in cells. Here, we investigate the function of ALYREF, an RNA export adapter associated with UAP56 and the THO complex, in R-loop regulation. We demonstrate that purified ALYREF promotes UAP56-mediated R-loop dissociation in vitro, and this stimulation is dependent on its interaction with UAP56 and R-loops. Importantly, we show that ALYREF binds DNA-RNA hybrids and R-loops. Consistently, ALYREF depletion causes R-loop accumulation and R-loop-mediated genome instability in cells. We propose that ALYREF, apart from its known role in RNA metabolism and export, is a key cellular R-loop coregulator, which binds R-loops and stimulates UAP56-driven resolution of unscheduled R-loops during transcription.This study was funded by the National Institute of General Medical Sciences and National Institute of Environmental Health Sciences of the National Institutes of Health under Award Number R15GM139135 and R21 ES028792, and startup funds and REP program from Texas State University (to X. X.), and the Spanish Agencia Estatal de Investigación (projects I + D + i PID2019-104270GB-I00/BMC from MCIN/AEI/10.13039/501100011033/and PID2022-138251NB-I00 from MICIU/AEI/10.13039/501100011033/and FEDER, UE), the European Research Council (ERC2014 AdG669898 TARLOOP) and Foundation ‘‘Vencer el Cáncer’’ (to A. A.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. C. G.-M was supported by predoctoral FPU contract from the Spanish Ministry of Education, Culture and Sports, and D. E. was supported by NIH R25 GM102783 Bridge to Doctorate Program.Peer reviewedAmerican Society for Biochemistry and Molecular BiologyElsevierNational Institute of General Medical Sciences (US)National Institute of Environmental Health Sciences (US)University of TexasAgencia Estatal de Investigación (España)Ministerio de Ciencia, Innovación y Universidades (España)Ministerio de Ciencia e Innovación (España)European Research CouncilEuropean CommissionFundación Vencer el CancerNational Institutes of Health (US)Ministerio de Educación, Cultura y Deporte (España)Guillén-Mendoza, Cristina [0000-0003-4396-4865]Luna, Rosa [0000-0002-6131-6610]Aguilera, Andrés [0000-0003-4782-1714]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202520252024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/378587https://api.elsevier.com/content/abstract/scopus_id/85211055351reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-104270GB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-138251NB-I00info:eu-repo/grantAgreement/EC/H2020/669898The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1016/j.jbc.2024.107996https://doi.org/10.1016/j.jbc.2024.107996Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3785872026-05-22T06:33:51Z
dc.title.none.fl_str_mv The molecular chaperone ALYREF promotes R-loop resolution and maintains genome stability
title The molecular chaperone ALYREF promotes R-loop resolution and maintains genome stability
spellingShingle The molecular chaperone ALYREF promotes R-loop resolution and maintains genome stability
Bhandari, Jay
ALYREF
DNA-RNA helicase
R-loop
TREX complex
UAP56
Genome instability
title_short The molecular chaperone ALYREF promotes R-loop resolution and maintains genome stability
title_full The molecular chaperone ALYREF promotes R-loop resolution and maintains genome stability
title_fullStr The molecular chaperone ALYREF promotes R-loop resolution and maintains genome stability
title_full_unstemmed The molecular chaperone ALYREF promotes R-loop resolution and maintains genome stability
title_sort The molecular chaperone ALYREF promotes R-loop resolution and maintains genome stability
dc.creator.none.fl_str_mv Bhandari, Jay
Guillén-Mendoza, Cristina
Banks, Kathryn
Eliaz, Lillian
Southwell, Sierra
Eyaa, Darriel
Luna, Rosa
Aguilera, Andrés
Xue, Xiaoyu
author Bhandari, Jay
author_facet Bhandari, Jay
Guillén-Mendoza, Cristina
Banks, Kathryn
Eliaz, Lillian
Southwell, Sierra
Eyaa, Darriel
Luna, Rosa
Aguilera, Andrés
Xue, Xiaoyu
author_role author
author2 Guillén-Mendoza, Cristina
Banks, Kathryn
Eliaz, Lillian
Southwell, Sierra
Eyaa, Darriel
Luna, Rosa
Aguilera, Andrés
Xue, Xiaoyu
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv National Institute of General Medical Sciences (US)
National Institute of Environmental Health Sciences (US)
University of Texas
Agencia Estatal de Investigación (España)
Ministerio de Ciencia, Innovación y Universidades (España)
Ministerio de Ciencia e Innovación (España)
European Research Council
European Commission
Fundación Vencer el Cancer
National Institutes of Health (US)
Ministerio de Educación, Cultura y Deporte (España)
Guillén-Mendoza, Cristina [0000-0003-4396-4865]
Luna, Rosa [0000-0002-6131-6610]
Aguilera, Andrés [0000-0003-4782-1714]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv ALYREF
DNA-RNA helicase
R-loop
TREX complex
UAP56
Genome instability
topic ALYREF
DNA-RNA helicase
R-loop
TREX complex
UAP56
Genome instability
description Unscheduled R-loops usually cause DNA damage and replication stress, and are therefore a major threat to genome stability. Several RNA processing factors, including the conserved THO complex and its associated RNA and DNA-RNA helicase UAP56, prevent R-loop accumulation in cells. Here, we investigate the function of ALYREF, an RNA export adapter associated with UAP56 and the THO complex, in R-loop regulation. We demonstrate that purified ALYREF promotes UAP56-mediated R-loop dissociation in vitro, and this stimulation is dependent on its interaction with UAP56 and R-loops. Importantly, we show that ALYREF binds DNA-RNA hybrids and R-loops. Consistently, ALYREF depletion causes R-loop accumulation and R-loop-mediated genome instability in cells. We propose that ALYREF, apart from its known role in RNA metabolism and export, is a key cellular R-loop coregulator, which binds R-loops and stimulates UAP56-driven resolution of unscheduled R-loops during transcription.
publishDate 2024
dc.date.none.fl_str_mv 2024
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/378587
https://api.elsevier.com/content/abstract/scopus_id/85211055351
url http://hdl.handle.net/10261/378587
https://api.elsevier.com/content/abstract/scopus_id/85211055351
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-104270GB-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-138251NB-I00
info:eu-repo/grantAgreement/EC/H2020/669898
The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1016/j.jbc.2024.107996
https://doi.org/10.1016/j.jbc.2024.107996
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology
Elsevier
publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology
Elsevier
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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