Depletion of the MFAP1/SPP381 Splicing Factor Causes R-Loop-Independent Genome Instability

THO/TREX is a conserved complex with a role in messenger ribonucleoprotein biogenesis that links gene expression and genome instability. Here, we show that human THO interacts with MFAP1 (microfibrillar-associated protein 1), a spliceosome-associated factor. Interestingly, MFAP1 depletion impairs ce...

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Detalles Bibliográficos
Autores: Salas-Armenteros, Irene, Barroso, Sonia, Rondón, Ana G., Pérez-Alegre, Mónica, Andújar, Eloísa, Luna, Rosa, Aguilera, Andrés
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/202545
Acceso en línea:http://hdl.handle.net/10261/202545
Access Level:acceso abierto
Palabra clave:Genome instability
THO complex
Alternative splicing
MFAP1/SPP381
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spelling Depletion of the MFAP1/SPP381 Splicing Factor Causes R-Loop-Independent Genome InstabilitySalas-Armenteros, IreneBarroso, SoniaRondón, Ana G.Pérez-Alegre, MónicaAndújar, EloísaLuna, RosaAguilera, AndrésGenome instabilityTHO complexAlternative splicingMFAP1/SPP381THO/TREX is a conserved complex with a role in messenger ribonucleoprotein biogenesis that links gene expression and genome instability. Here, we show that human THO interacts with MFAP1 (microfibrillar-associated protein 1), a spliceosome-associated factor. Interestingly, MFAP1 depletion impairs cell proliferation and genome integrity, increasing γH2AX foci and DNA breaks. This phenotype is not dependent on either transcription or RNA-DNA hybrids. Mutations in the yeast orthologous gene SPP381 cause similar transcription-independent genome instability, supporting a conserved role. MFAP1 depletion has a wide effect on splicing and gene expression in human cells, determined by transcriptome analyses. MFAP1 depletion affects a number of DNA damage response (DDR) genes, which supports an indirect role of MFAP1 on genome integrity. Our work defines a functional interaction between THO and RNA processing and argues that splicing factors may contribute to genome integrity indirectly by regulating the expression of DDR genes rather than by a direct role. THO, an mRNA biogenesis factor, interacts with MFAP1, a conserved spliceosome-associated protein. Salas-Armenteros et al. show that MFAP1/SPP381 depletion alters splicing and gene expression and increases genome instability in an RNA-DNA hybrid-independent manner. Therefore, RNA-DNA hybrid accumulation is not an intrinsic consequence of splicing defects.Research was funded by the European Research Council (grant ERC2014 AdG669898 TARLOOP), the Spanish Ministry of Economy and Competitiveness (grant BFU2016-75058-P), the Junta de Andalucía Spain (grant BIO1238), and the European Union Regional Funds (FEDER). I.S.-A. was a recipient of a FPU pre-doctoral training grant from the Spanish Ministry of Education, Culture and Sports.Elsevier BVEuropean Research CouncilMinisterio de Economía y Competitividad (España)Junta de AndalucíaEuropean CommissionMinisterio de Educación, Cultura y Deporte (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2020202020192020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/202545reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/EC/H2020/669898info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2016-75058-Phttp://dx.doi.org/10.1016/j.celrep.2019.07.010Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2025452026-05-22T06:33:51Z
dc.title.none.fl_str_mv Depletion of the MFAP1/SPP381 Splicing Factor Causes R-Loop-Independent Genome Instability
title Depletion of the MFAP1/SPP381 Splicing Factor Causes R-Loop-Independent Genome Instability
spellingShingle Depletion of the MFAP1/SPP381 Splicing Factor Causes R-Loop-Independent Genome Instability
Salas-Armenteros, Irene
Genome instability
THO complex
Alternative splicing
MFAP1/SPP381
title_short Depletion of the MFAP1/SPP381 Splicing Factor Causes R-Loop-Independent Genome Instability
title_full Depletion of the MFAP1/SPP381 Splicing Factor Causes R-Loop-Independent Genome Instability
title_fullStr Depletion of the MFAP1/SPP381 Splicing Factor Causes R-Loop-Independent Genome Instability
title_full_unstemmed Depletion of the MFAP1/SPP381 Splicing Factor Causes R-Loop-Independent Genome Instability
title_sort Depletion of the MFAP1/SPP381 Splicing Factor Causes R-Loop-Independent Genome Instability
dc.creator.none.fl_str_mv Salas-Armenteros, Irene
Barroso, Sonia
Rondón, Ana G.
Pérez-Alegre, Mónica
Andújar, Eloísa
Luna, Rosa
Aguilera, Andrés
author Salas-Armenteros, Irene
author_facet Salas-Armenteros, Irene
Barroso, Sonia
Rondón, Ana G.
Pérez-Alegre, Mónica
Andújar, Eloísa
Luna, Rosa
Aguilera, Andrés
author_role author
author2 Barroso, Sonia
Rondón, Ana G.
Pérez-Alegre, Mónica
Andújar, Eloísa
Luna, Rosa
Aguilera, Andrés
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv European Research Council
Ministerio de Economía y Competitividad (España)
Junta de Andalucía
European Commission
Ministerio de Educación, Cultura y Deporte (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Genome instability
THO complex
Alternative splicing
MFAP1/SPP381
topic Genome instability
THO complex
Alternative splicing
MFAP1/SPP381
description THO/TREX is a conserved complex with a role in messenger ribonucleoprotein biogenesis that links gene expression and genome instability. Here, we show that human THO interacts with MFAP1 (microfibrillar-associated protein 1), a spliceosome-associated factor. Interestingly, MFAP1 depletion impairs cell proliferation and genome integrity, increasing γH2AX foci and DNA breaks. This phenotype is not dependent on either transcription or RNA-DNA hybrids. Mutations in the yeast orthologous gene SPP381 cause similar transcription-independent genome instability, supporting a conserved role. MFAP1 depletion has a wide effect on splicing and gene expression in human cells, determined by transcriptome analyses. MFAP1 depletion affects a number of DNA damage response (DDR) genes, which supports an indirect role of MFAP1 on genome integrity. Our work defines a functional interaction between THO and RNA processing and argues that splicing factors may contribute to genome integrity indirectly by regulating the expression of DDR genes rather than by a direct role. THO, an mRNA biogenesis factor, interacts with MFAP1, a conserved spliceosome-associated protein. Salas-Armenteros et al. show that MFAP1/SPP381 depletion alters splicing and gene expression and increases genome instability in an RNA-DNA hybrid-independent manner. Therefore, RNA-DNA hybrid accumulation is not an intrinsic consequence of splicing defects.
publishDate 2019
dc.date.none.fl_str_mv 2019
2020
2020
2020
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/10261/202545
url http://hdl.handle.net/10261/202545
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#
info:eu-repo/grantAgreement/EC/H2020/669898
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2016-75058-P
http://dx.doi.org/10.1016/j.celrep.2019.07.010
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier BV
publisher.none.fl_str_mv Elsevier BV
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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score 15.811543

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