van der Lelij, PetraLieb, SimoneJude, JulianWutz, GordanaSantos, Catarina P.Falkenberg, KatrinaSchlattl, AndreasBan, JozefSchwentner, RaphaelaHoffmann, ThomasKovar, HeinrichReal, Francisco X.Waldman, ToddPearson, Mark A.Kraut, NorbertPeters, Jan-MichaelZuber, JohannesPetronczki, Mark2017-11-142017-11-142017van 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;6:e26980. DOI: 10.7554/eLife.269802050-084Xhttp://hdl.handle.net/10230/33224Recent 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.application/pdfeng© 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.info:eu-repo/semantics/articlehttp://dx.doi.org/10.7554/eLife.26980Cancer biologyCell biologyCell divisionChromosomesCohesinGenetic interactionHumanMitosisSynthetic lethalityinfo:eu-repo/semantics/openAccess