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

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, STAG...

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Autores: van der Lelij, Petra, Lieb, Simone, Jude, Julian, Wutz, Gordana, Santos, Catarina P, Falkenberg, Katrina, Schlattl, Andreas, Ban, Jozef, Schwentner, Raphaela, Hoffmann, Thomas, Kovar, Heinrich, Real Arribas, Francisco, Waldman, Todd, Pearson, Mark A, Kraut, Norbert, Peters, Jan-Michael, Zuber, Johannes, Petronczki, Mark
Tipo de recurso: artículo
Fecha de publicación:2017
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/7110
Acceso en línea:http://hdl.handle.net/20.500.12105/7110
Access Level:acceso abierto
Palabra clave:Antigens, Nuclear
Cell Division
Cell Line, Tumor
Cell Survival
Humans
Nuclear Proteins
Synthetic Lethal Mutations
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spelling Synthetic lethality between the cohesin subunits STAG1 and STAG2 in diverse cancer contextsvan der Lelij, PetraLieb, SimoneJude, JulianWutz, GordanaSantos, Catarina PFalkenberg, KatrinaSchlattl, AndreasBan, JozefSchwentner, RaphaelaHoffmann, ThomasKovar, HeinrichReal Arribas, FranciscoWaldman, ToddPearson, Mark AKraut, NorbertPeters, Jan-MichaelZuber, JohannesPetronczki, MarkAntigens, NuclearCell DivisionCell Line, TumorCell SurvivalHumansNuclear ProteinsSynthetic Lethal MutationsRecent 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.eLife Sciences PublicationsFWF Austrian Science FundAustrian Research Promotion AgencyUnión Europea. Comisión Europea. European Research Council (ERC)Asociación Española Contra el CáncerNational Institutes of Health (Estados Unidos)20192019-02-0520172017-01-0120172017-01-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/20.500.12105/7110reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)InglésengEuropean Commission http://dx.doi.org/10.13039/501100000780 Seventh Framework Programme 336860European Commission http://dx.doi.org/10.13039/501100000780 Seventh Framework Programme SFB F4710open accesshttp://purl.org/coar/access_right/c_abf2Atribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/71102026-06-12T12:43:37Z
dc.title.none.fl_str_mv Synthetic lethality between the cohesin subunits STAG1 and STAG2 in diverse cancer contexts
title Synthetic lethality between the cohesin subunits STAG1 and STAG2 in diverse cancer contexts
spellingShingle Synthetic lethality between the cohesin subunits STAG1 and STAG2 in diverse cancer contexts
van der Lelij, Petra
Antigens, Nuclear
Cell Division
Cell Line, Tumor
Cell Survival
Humans
Nuclear Proteins
Synthetic Lethal Mutations
title_short Synthetic lethality between the cohesin subunits STAG1 and STAG2 in diverse cancer contexts
title_full Synthetic lethality between the cohesin subunits STAG1 and STAG2 in diverse cancer contexts
title_fullStr Synthetic lethality between the cohesin subunits STAG1 and STAG2 in diverse cancer contexts
title_full_unstemmed Synthetic lethality between the cohesin subunits STAG1 and STAG2 in diverse cancer contexts
title_sort Synthetic lethality between the cohesin subunits STAG1 and STAG2 in diverse cancer contexts
dc.creator.none.fl_str_mv van der Lelij, Petra
Lieb, Simone
Jude, Julian
Wutz, Gordana
Santos, Catarina P
Falkenberg, Katrina
Schlattl, Andreas
Ban, Jozef
Schwentner, Raphaela
Hoffmann, Thomas
Kovar, Heinrich
Real Arribas, Francisco
Waldman, Todd
Pearson, Mark A
Kraut, Norbert
Peters, Jan-Michael
Zuber, Johannes
Petronczki, Mark
author van der Lelij, Petra
author_facet van der Lelij, Petra
Lieb, Simone
Jude, Julian
Wutz, Gordana
Santos, Catarina P
Falkenberg, Katrina
Schlattl, Andreas
Ban, Jozef
Schwentner, Raphaela
Hoffmann, Thomas
Kovar, Heinrich
Real Arribas, Francisco
Waldman, Todd
Pearson, Mark A
Kraut, Norbert
Peters, Jan-Michael
Zuber, Johannes
Petronczki, Mark
author_role author
author2 Lieb, Simone
Jude, Julian
Wutz, Gordana
Santos, Catarina P
Falkenberg, Katrina
Schlattl, Andreas
Ban, Jozef
Schwentner, Raphaela
Hoffmann, Thomas
Kovar, Heinrich
Real Arribas, Francisco
Waldman, Todd
Pearson, Mark A
Kraut, Norbert
Peters, Jan-Michael
Zuber, Johannes
Petronczki, Mark
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv FWF Austrian Science Fund
Austrian Research Promotion Agency
Unión Europea. Comisión Europea. European Research Council (ERC)
Asociación Española Contra el Cáncer
National Institutes of Health (Estados Unidos)
dc.subject.none.fl_str_mv Antigens, Nuclear
Cell Division
Cell Line, Tumor
Cell Survival
Humans
Nuclear Proteins
Synthetic Lethal Mutations
topic Antigens, Nuclear
Cell Division
Cell Line, Tumor
Cell Survival
Humans
Nuclear Proteins
Synthetic Lethal Mutations
description 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.
publishDate 2017
dc.date.none.fl_str_mv 2017
2017-01-01
2017
2017-01-01
2019
2019-02-05
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/7110
url http://hdl.handle.net/20.500.12105/7110
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv European Commission http://dx.doi.org/10.13039/501100000780 Seventh Framework Programme 336860
European Commission http://dx.doi.org/10.13039/501100000780 Seventh Framework Programme SFB F4710
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv eLife Sciences Publications
publisher.none.fl_str_mv eLife Sciences Publications
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869407238907494400
score 15,811543

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