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Synthetic lethality between the cohesin subunits STAG1 and STAG2 in diverse cancer contexts

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dc.contributor.authorvan der Lelij, Petra
dc.contributor.authorLieb, Simone
dc.contributor.authorJude, Julian
dc.contributor.authorWutz, Gordana
dc.contributor.authorSantos, Catarina P
dc.contributor.authorFalkenberg, Katrina
dc.contributor.authorSchlattl, Andreas
dc.contributor.authorBan, Jozef
dc.contributor.authorSchwentner, Raphaela
dc.contributor.authorHoffmann, Thomas
dc.contributor.authorKovar, Heinrich
dc.contributor.authorReal Arribas, Francisco
dc.contributor.authorWaldman, Todd
dc.contributor.authorPearson, Mark A
dc.contributor.authorKraut, Norbert
dc.contributor.authorPeters, Jan-Michael
dc.contributor.authorZuber, Johannes
dc.contributor.authorPetronczki, Mark
dc.contributor.funderFWF Austrian Science Fund
dc.contributor.funderAustrian Research Promotion Agency
dc.contributor.funderUnión Europea. Comisión Europea. European Research Council (ERC)
dc.contributor.funderAsociación Española Contra el Cáncer
dc.contributor.funderNational Institutes of Health (Estados Unidos)
dc.date.accessioned2019-02-05T11:33:32Z
dc.date.available2019-02-05T11:33:32Z
dc.date.issued2017
dc.description.abstractRecent genome analyses have identified recurrent mutations in the cohesin complex in a wide range of human cancers. Here we demonstrate that the most frequently mutated subunit of the cohesin complex, STAG2, displays a strong synthetic lethal interaction with its paralog STAG1. Mechanistically, STAG1 loss abrogates sister chromatid cohesion in STAG2 mutated but not in wild-type cells leading to mitotic catastrophe, defective cell division and apoptosis. STAG1 inactivation inhibits the proliferation of STAG2 mutated but not wild-type bladder cancer and Ewing sarcoma cell lines. Restoration of STAG2 expression in a mutated bladder cancer model alleviates the dependency on STAG1. Thus, STAG1 and STAG2 support sister chromatid cohesion to redundantly ensure cell survival. STAG1 represents a vulnerability of cancer cells carrying mutations in the major emerging tumor suppressor STAG2 across different cancer contexts. Exploiting synthetic lethal interactions to target recurrent cohesin mutations in cancer, e.g. by inhibiting STAG1, holds the promise for the development of selective therapeutics.es_ES
dc.description.peerreviewedSíes_ES
dc.description.sponsorshipWe would like to thank Monika Kriz and Renate Schnitzer for clonal analysis. The IMP is supported by Boehringer Ingelheim. Research in the laboratory of J-MP is funded by the Austrian Science Fund (SFB-F34 and Wittgenstein award Z196-B20) and the Austrian Research Promotion Agency (Head- quarter grants FFG-834223 and FFG-852936, Laura Bassi Centre for Optimized Structural Studies grant FFG-840283). Research in the laboratory of JZ was funded by a Starting Grant of the European Research Council (ERC no. 336860) and SFB grant F4710 of the Austrian Science Fund (FWF). Research on Ewing sarcoma in the laboratory of HK was funded by the Austrian Science Fund ERA- Net grant I 1225-B19. Work in the lab of FXR was funded by a grant from Fundacio´ n Cientı´fica de la Asociacio´ n Espan˜ ola Contra el Ca´ ncer, Madrid, Spain. Research in the laboratory of TW is supported by National Institute of Health grant R01CA169345 and an Innovation Grant from Alex’s Lemonade Standes_ES
dc.format.volume6es_ES
dc.identifier.citationElife. 2017;6. pii: e26980es_ES
dc.identifier.doi10.7554/eLife.26980es_ES
dc.identifier.e-issn2050-084Xes_ES
dc.identifier.issn2050-084Xes_ES
dc.identifier.journaleLifees_ES
dc.identifier.pubmedID28691904es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/7110
dc.language.isoenges_ES
dc.publishereLife Sciences Publicationses_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7/336860es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7/SFB F4710es_ES
dc.relation.publisherversionhttps://doi.org/10.7554/eLife.26980.es_ES
dc.repisalud.institucionCNIOes_ES
dc.repisalud.orgCNIOCNIO::Grupos de investigación::Grupo de Carcinogénesis Epiteliales_ES
dc.rights.accessRightsopen accesses_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectCancer biologyes_ES
dc.subjectCell biologyes_ES
dc.subjectCell divisiones_ES
dc.subjectChromosomeses_ES
dc.subjectCohesines_ES
dc.subjectGenetic interactiones_ES
dc.subjectHumanes_ES
dc.subjectMitosises_ES
dc.subjectSynthetic lethalityes_ES
dc.subject.meshAntigens, Nucleares_ES
dc.subject.meshCell Divisiones_ES
dc.subject.meshCell Line, Tumores_ES
dc.subject.meshCell Survivales_ES
dc.subject.meshHumanses_ES
dc.subject.meshNuclear Proteinses_ES
dc.subject.meshSynthetic Lethal Mutationses_ES
dc.titleSynthetic lethality between the cohesin subunits STAG1 and STAG2 in diverse cancer contextses_ES
dc.typejournal articlees_ES
dc.type.hasVersionVoRes_ES
dspace.entity.typePublication
relation.isAuthorOfPublication62d13a40-e75d-49b1-bb0a-f54a4146ad3e
relation.isAuthorOfPublication.latestForDiscovery62d13a40-e75d-49b1-bb0a-f54a4146ad3e
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