Splicing events in the control of genome integrity: role of SLU7 and truncated SRSF3 proteins

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dc.contributor.authorJiménez, Maddalen
dc.contributor.authorUrtasun Alonso, Raquel
dc.contributor.authorElizalde, María
dc.contributor.authorAzkona, María
dc.contributor.authorLatasa, Maria Ujue
dc.contributor.authorUriarte, Iker
dc.contributor.authorArechederra, María
dc.contributor.authorAlignani, Diego
dc.contributor.authorBárcena-Varela, Marina
dc.contributor.authorÁlvarez-Sola, Gloria
dc.contributor.authorColyn, Leticia
dc.contributor.authorSantamaría, Eva
dc.contributor.authorSangro, Bruno
dc.contributor.authorRodriguez-Ortigosa, Carlos
dc.contributor.authorFernández-Barrena, Maite G.
dc.contributor.authorÁvila, Matías A.
dc.contributor.authorBerasain, Carmen
dc.contributor.departmentCiencias de la Saludes_ES
dc.contributor.departmentOsasun Zientziakeu
dc.date.accessioned2024-01-19T10:32:15Z
dc.date.available2024-01-19T10:32:15Z
dc.date.issued2019
dc.date.updated2024-01-19T08:51:19Z
dc.description.abstractGenome instability is related to disease development and carcinogenesis. DNA lesions are caused by genotoxic compounds but also by the dysregulation of fundamental processes like transcription, DNA replication and mitosis. Recent evidence indicates that impaired expression of RNA-binding proteins results in mitotic aberrations and the formation of transcription-associated RNA-DNA hybrids (R-loops), events strongly associated with DNA injury. We identify the splicing regulator SLU7 as a key mediator of genome stability. SLU7 knockdown results in R-loops formation, DNA damage, cell-cycle arrest and severe mitotic derangements with loss of sister chromatid cohesion (SCC). We define a molecular pathway through which SLU7 keeps in check the generation of truncated forms of the splicing factor SRSF3 (SRp20) (SRSF3-TR). Behaving as dominant negative, or by gain-of-function, SRSF3-TR impair the correct splicing and expression of the splicing regulator SRSF1 (ASF/SF2) and the crucial SCC protein sororin. This unique function of SLU7 was found in cancer cells of different tissue origin and also in the normal mouse liver, demonstrating a conserved and fundamental role of SLU7 in the preservation of genome integrity. Therefore, the dowregulation of SLU7 and the alterations of this pathway that we observe in the cirrhotic liver could be involved in the process of hepatocarcinogenesis.en
dc.description.sponsorshipCIBERehd; Instituto de Salud Carlos III (ISCIII) [PI13/00359, PI13/00385]; MINECO/AEI/FEDER,UE [SAF2016-75972-R]; HEPACARE Project from Fundación La Caixa; Ministerio de Educación FPI Fellowship, Cultura y Deporte; ADA-UNAV and CIMA Fellowships; AECC Post-doctoral Fellowship; Fundación Eugenio Rodríguez Pascual; Fundación Echebano; Fundación Mario Losantos; Fundación M Torres and Mrs Eduardo Ávila and Sergio Durá contribution. Funding for open access charge: MINECO/AEI/FEDER,UE [SAF2016-75972-R].en
dc.format.mimetypeapplication/pdfen
dc.identifier.citationJiménez, M., Urtasun, R., Elizalde, M., Azkona, M., Latasa, M.U., Uriarte, I., Arechederra, M., Alignani, D., Bárcena-Varela, M., Alvarez-Sola, G., Colyn, L., Santamaría, E., Sangro, B., Rodriguez-Ortigosa, C., Fernandez-Barrena, M.G., Ávila, M.A., Berasain, C. (2019) Splicing events in the control of genome integrity: Role of SLU7 and truncated SRSF3 proteins. Nucleic acids research, 47(7), 3450-3466. https://doi.org/10.1093/nar/gkz014.en
dc.identifier.doi10.1093/nar/gkz014
dc.identifier.issn0305-1048
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/47101
dc.language.isoengen
dc.publisherOxford University Pressen
dc.relation.ispartofNucleic Acids Research, 47 (7) 3450-3466en
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO//PI13%2F00359/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO//PI13%2F00385/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO//SAF2016- 75972-R/
dc.relation.publisherversionhttps://doi.org/10.1093/nar/gkz014
dc.rights©The Author(s) 2019. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License.en
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by-nc/4.0/
dc.subjectSLU7en
dc.subjectSRSF3en
dc.titleSplicing events in the control of genome integrity: role of SLU7 and truncated SRSF3 proteinsen
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublication
relation.isAuthorOfPublication64ffa81f-666a-4086-80fb-a1f290644a67
relation.isAuthorOfPublication.latestForDiscovery64ffa81f-666a-4086-80fb-a1f290644a67

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