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

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dc.contributor.author van der Lelij, Petra
dc.contributor.author Lieb, Simone
dc.contributor.author Jude, Julian
dc.contributor.author Wutz, Gordana
dc.contributor.author Santos, Catarina P.
dc.contributor.author Falkenberg, Katrina
dc.contributor.author Schlattl, Andreas
dc.contributor.author Ban, Jozef
dc.contributor.author Schwentner, Raphaela
dc.contributor.author Hoffmann, Thomas
dc.contributor.author Kovar, Heinrich
dc.contributor.author Real, Francisco X.
dc.contributor.author Waldman, Todd
dc.contributor.author Pearson, Mark A.
dc.contributor.author Kraut, Norbert
dc.contributor.author Peters, Jan-Michael
dc.contributor.author Zuber, Johannes
dc.contributor.author Petronczki, Mark
dc.date.accessioned 2017-11-14T16:22:44Z
dc.date.available 2017-11-14T16:22:44Z
dc.date.issued 2017
dc.identifier.citation van der Lelij P, Lieb S, Jude J, Wutz G, Santos CP, Falkenberg K, et al. Synthetic lethality between the cohesin subunits STAG1 and STAG2 in diverse cancer contexts. Elife. 2017 Jul 10;6. pii: e26980. DOI: 10.7554/eLife.26980
dc.identifier.issn 2050-084X
dc.identifier.uri http://hdl.handle.net/10230/33224
dc.description.abstract Recent 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.
dc.description.sponsorship 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 (Headquarter 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 Fundación Científica de la Asociación Española Contra el Cáncer, 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 Stand.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher eLife
dc.relation.ispartof Elife. 2017 Jul 10;6. pii: e26980
dc.rights © van der Lelij et al. This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use and redistribution provided that the original author and source are credited.
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.title Synthetic lethality between the cohesin subunits STAG1 and STAG2 in diverse cancer contexts
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.7554/eLife.26980
dc.subject.keyword Cancer biology
dc.subject.keyword Cell biology
dc.subject.keyword Cell division
dc.subject.keyword Chromosomes
dc.subject.keyword Cohesin
dc.subject.keyword Genetic interaction
dc.subject.keyword Human
dc.subject.keyword Mitosis
dc.subject.keyword Synthetic lethality
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/336860
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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