Identification of and molecular basis for SIRT6 loss-of-function point mutations in cancer

Autores
Kugel, Sita; Feldman, Jessica L.; Klein, Mark A.; Silberman, Dafne Magali; Sebastián, Carlos; Mermel, Craig; Dobersch, Stephanie; Clark, Abbe R.; Getz, Gad; Denu, John M.; Mostoslavsky, Raul
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Chromatin factors have emerged as the most frequently dysregulated family of proteins in cancer. We have previously identified the histone deacetylase SIRT6 as a key tumor suppressor, yet whether point mutations are selected for in cancer remains unclear. In this manuscript, we characterized naturally occurring patient-derived SIRT6 mutations. Strikingly, all the mutations significantly affected either stability or catalytic activity of SIRT6, indicating that these mutations were selected for in these tumors. Further, the mutant proteins failed to rescue sirt6 knockout (SIRT6 KO) cells, as measured by the levels of histone acetylation at glycolytic genes and their inability to rescue the tumorigenic potential of these cells. Notably, the main activity affected in the mutants was histone deacetylation rather than demyristoylation, pointing to the former as the main tumor-suppressive function for SIRT6. Our results identified cancer-associated point mutations in SIRT6, cementing its function as a tumor suppressor in human cancer.
Fil: Kugel, Sita. Harvard Medical School; Estados Unidos
Fil: Feldman, Jessica L.. University Of Wisconsin; Estados Unidos
Fil: Klein, Mark A.. University Of Wisconsin; Estados Unidos
Fil: Silberman, Dafne Magali. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina
Fil: Sebastián, Carlos. Harvard Medical School; Estados Unidos
Fil: Mermel, Craig. Harvard Medical School; Estados Unidos
Fil: Dobersch, Stephanie. Institute Max Planck for Heart and Lung Research; Alemania
Fil: Clark, Abbe R.. Harvard Medical School; Estados Unidos
Fil: Getz, Gad. Harvard Medical School; Estados Unidos
Fil: Denu, John M.. University Of Wisconsin; Estados Unidos
Fil: Mostoslavsky, Raul. Harvard Medical School; Estados Unidos
Materia
Sirt6
Genetic
Cancer
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/13585
Acceder
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repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Identification of and molecular basis for SIRT6 loss-of-function point mutations in cancerKugel, SitaFeldman, Jessica L.Klein, Mark A.Silberman, Dafne MagaliSebastián, CarlosMermel, CraigDobersch, StephanieClark, Abbe R.Getz, GadDenu, John M.Mostoslavsky, RaulSirt6GeneticCancerhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Chromatin factors have emerged as the most frequently dysregulated family of proteins in cancer. We have previously identified the histone deacetylase SIRT6 as a key tumor suppressor, yet whether point mutations are selected for in cancer remains unclear. In this manuscript, we characterized naturally occurring patient-derived SIRT6 mutations. Strikingly, all the mutations significantly affected either stability or catalytic activity of SIRT6, indicating that these mutations were selected for in these tumors. Further, the mutant proteins failed to rescue sirt6 knockout (SIRT6 KO) cells, as measured by the levels of histone acetylation at glycolytic genes and their inability to rescue the tumorigenic potential of these cells. Notably, the main activity affected in the mutants was histone deacetylation rather than demyristoylation, pointing to the former as the main tumor-suppressive function for SIRT6. Our results identified cancer-associated point mutations in SIRT6, cementing its function as a tumor suppressor in human cancer.Fil: Kugel, Sita. Harvard Medical School; Estados UnidosFil: Feldman, Jessica L.. University Of Wisconsin; Estados UnidosFil: Klein, Mark A.. University Of Wisconsin; Estados UnidosFil: Silberman, Dafne Magali. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Sebastián, Carlos. Harvard Medical School; Estados UnidosFil: Mermel, Craig. Harvard Medical School; Estados UnidosFil: Dobersch, Stephanie. Institute Max Planck for Heart and Lung Research; AlemaniaFil: Clark, Abbe R.. Harvard Medical School; Estados UnidosFil: Getz, Gad. Harvard Medical School; Estados UnidosFil: Denu, John M.. University Of Wisconsin; Estados UnidosFil: Mostoslavsky, Raul. Harvard Medical School; Estados UnidosElsevier Inc2015-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/13585Kugel, Sita ; Feldman, Jessica L. ; Klein, Mark A.; Silberman, Dafne Magali; Sebastián, Carlos; et al.; Identification of and molecular basis for SIRT6 loss-of-function point mutations in cancer; Elsevier Inc; Cell Reports; 13; 3; 10-2015; 479-4882211-1247enginfo:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S2211124715010335info:eu-repo/semantics/altIdentifier/doi/10.1016/j.celrep.2015.09.022info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618237/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:36:38Zoai:ri.conicet.gov.ar:11336/13585instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:36:38.559CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Identification of and molecular basis for SIRT6 loss-of-function point mutations in cancer
title Identification of and molecular basis for SIRT6 loss-of-function point mutations in cancer
spellingShingle Identification of and molecular basis for SIRT6 loss-of-function point mutations in cancer
Kugel, Sita
Sirt6
Genetic
Cancer
title_short Identification of and molecular basis for SIRT6 loss-of-function point mutations in cancer
title_full Identification of and molecular basis for SIRT6 loss-of-function point mutations in cancer
title_fullStr Identification of and molecular basis for SIRT6 loss-of-function point mutations in cancer
title_full_unstemmed Identification of and molecular basis for SIRT6 loss-of-function point mutations in cancer
title_sort Identification of and molecular basis for SIRT6 loss-of-function point mutations in cancer
dc.creator.none.fl_str_mv Kugel, Sita
Feldman, Jessica L.
Klein, Mark A.
Silberman, Dafne Magali
Sebastián, Carlos
Mermel, Craig
Dobersch, Stephanie
Clark, Abbe R.
Getz, Gad
Denu, John M.
Mostoslavsky, Raul
author Kugel, Sita
author_facet Kugel, Sita
Feldman, Jessica L.
Klein, Mark A.
Silberman, Dafne Magali
Sebastián, Carlos
Mermel, Craig
Dobersch, Stephanie
Clark, Abbe R.
Getz, Gad
Denu, John M.
Mostoslavsky, Raul
author_role author
author2 Feldman, Jessica L.
Klein, Mark A.
Silberman, Dafne Magali
Sebastián, Carlos
Mermel, Craig
Dobersch, Stephanie
Clark, Abbe R.
Getz, Gad
Denu, John M.
Mostoslavsky, Raul
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Sirt6
Genetic
Cancer
topic Sirt6
Genetic
Cancer
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Chromatin factors have emerged as the most frequently dysregulated family of proteins in cancer. We have previously identified the histone deacetylase SIRT6 as a key tumor suppressor, yet whether point mutations are selected for in cancer remains unclear. In this manuscript, we characterized naturally occurring patient-derived SIRT6 mutations. Strikingly, all the mutations significantly affected either stability or catalytic activity of SIRT6, indicating that these mutations were selected for in these tumors. Further, the mutant proteins failed to rescue sirt6 knockout (SIRT6 KO) cells, as measured by the levels of histone acetylation at glycolytic genes and their inability to rescue the tumorigenic potential of these cells. Notably, the main activity affected in the mutants was histone deacetylation rather than demyristoylation, pointing to the former as the main tumor-suppressive function for SIRT6. Our results identified cancer-associated point mutations in SIRT6, cementing its function as a tumor suppressor in human cancer.
Fil: Kugel, Sita. Harvard Medical School; Estados Unidos
Fil: Feldman, Jessica L.. University Of Wisconsin; Estados Unidos
Fil: Klein, Mark A.. University Of Wisconsin; Estados Unidos
Fil: Silberman, Dafne Magali. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina
Fil: Sebastián, Carlos. Harvard Medical School; Estados Unidos
Fil: Mermel, Craig. Harvard Medical School; Estados Unidos
Fil: Dobersch, Stephanie. Institute Max Planck for Heart and Lung Research; Alemania
Fil: Clark, Abbe R.. Harvard Medical School; Estados Unidos
Fil: Getz, Gad. Harvard Medical School; Estados Unidos
Fil: Denu, John M.. University Of Wisconsin; Estados Unidos
Fil: Mostoslavsky, Raul. Harvard Medical School; Estados Unidos
description Chromatin factors have emerged as the most frequently dysregulated family of proteins in cancer. We have previously identified the histone deacetylase SIRT6 as a key tumor suppressor, yet whether point mutations are selected for in cancer remains unclear. In this manuscript, we characterized naturally occurring patient-derived SIRT6 mutations. Strikingly, all the mutations significantly affected either stability or catalytic activity of SIRT6, indicating that these mutations were selected for in these tumors. Further, the mutant proteins failed to rescue sirt6 knockout (SIRT6 KO) cells, as measured by the levels of histone acetylation at glycolytic genes and their inability to rescue the tumorigenic potential of these cells. Notably, the main activity affected in the mutants was histone deacetylation rather than demyristoylation, pointing to the former as the main tumor-suppressive function for SIRT6. Our results identified cancer-associated point mutations in SIRT6, cementing its function as a tumor suppressor in human cancer.
publishDate 2015
dc.date.none.fl_str_mv 2015-10
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/13585
Kugel, Sita ; Feldman, Jessica L. ; Klein, Mark A.; Silberman, Dafne Magali; Sebastián, Carlos; et al.; Identification of and molecular basis for SIRT6 loss-of-function point mutations in cancer; Elsevier Inc; Cell Reports; 13; 3; 10-2015; 479-488
2211-1247
url http://hdl.handle.net/11336/13585
identifier_str_mv Kugel, Sita ; Feldman, Jessica L. ; Klein, Mark A.; Silberman, Dafne Magali; Sebastián, Carlos; et al.; Identification of and molecular basis for SIRT6 loss-of-function point mutations in cancer; Elsevier Inc; Cell Reports; 13; 3; 10-2015; 479-488
2211-1247
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S2211124715010335
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.celrep.2015.09.022
info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618237/
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier Inc
publisher.none.fl_str_mv Elsevier Inc
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1844613150881611776
score 13.070432

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