Transcriptional Autoregulation by BRCA1

Autores
de Siervi, Adriana; de Luca, Paola; Byun, Jung S.; Di, Li Jun; Fufa, Temesgen; Haggerty, Cynthia M.; Vazquez, Elba Susana; Moiola, Cristian Pablo; Longo, Dan L.; Gardner, Kevin
Año de publicación
2010
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The BRCA1 gene product plays numerous roles in regulating genome integrity. Its role in assembling supermolecular complexes in response to DNA damage has been extensively studied; however, much less is understood about its role as a transcriptional coregulator. Loss or mutation is associated with hereditary breast and ovarian cancers, whereas altered expression occurs frequently in sporadic forms of breast cancer, suggesting that the control of BRCA1 transcription might be important to tumorigenesis. Here, we provide evidence of a striking linkage between the roles for BRCA1 as a transcriptional coregulator with control of its expression via an autoregulatory transcriptional loop. BRCA1 assembles with complexes containing E2F-1 and RB to form a repressive multicomponent transcriptional complex that inhibits BRCA1 promoter transcription. This complex is disrupted by genotoxic stress, resulting in the displacement of BRCA1 protein from the BRCA1 promoter and subsequent upregulation of BRCA1 transcription. Cells depleted of BRCA1 respond by upregulating BRCA1 transcripts, whereas cells overexpressing BRCA1 respond by downregulating BRCA1 transcripts. Tandem chromatin immmunoprecipitation studies show that BRCA1 is regulated by a dynamic coregulatory complex containing BRCA1, E2F1, and Rb at the BRCA1 promoter that is disrupted by DNA-damaging agents to increase its transcription. These results define a novel transcriptional mechanism of autoregulated homeostasis of BRCA1 that selectively titrates its levels to maintain genome integrity in response to genotoxic insult.
Fil: de Siervi, Adriana. National Cancer Institute; Estados Unidos. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: de Luca, Paola. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Byun, Jung S.. National Cancer Institute; Estados Unidos
Fil: Di, Li Jun. National Cancer Institute; Estados Unidos
Fil: Fufa, Temesgen. National Cancer Institute; Estados Unidos
Fil: Haggerty, Cynthia M.. National Cancer Institute; Estados Unidos
Fil: Vazquez, Elba Susana. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Moiola, Cristian Pablo. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Longo, Dan L.. National Institute on Aging; Estados Unidos
Fil: Gardner, Kevin. National Cancer Institute; Estados Unidos
Materia
Brca1
Transcripción
Daño en El Adn
Ciclo Celular
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/16581
Acceder
id CONICETDig_b6a109e214890b146665e6e62cb47fdc
oai_identifier_str oai:ri.conicet.gov.ar:11336/16581
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Transcriptional Autoregulation by BRCA1de Siervi, Adrianade Luca, PaolaByun, Jung S.Di, Li JunFufa, TemesgenHaggerty, Cynthia M.Vazquez, Elba SusanaMoiola, Cristian PabloLongo, Dan L.Gardner, KevinBrca1TranscripciónDaño en El AdnCiclo Celularhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The BRCA1 gene product plays numerous roles in regulating genome integrity. Its role in assembling supermolecular complexes in response to DNA damage has been extensively studied; however, much less is understood about its role as a transcriptional coregulator. Loss or mutation is associated with hereditary breast and ovarian cancers, whereas altered expression occurs frequently in sporadic forms of breast cancer, suggesting that the control of BRCA1 transcription might be important to tumorigenesis. Here, we provide evidence of a striking linkage between the roles for BRCA1 as a transcriptional coregulator with control of its expression via an autoregulatory transcriptional loop. BRCA1 assembles with complexes containing E2F-1 and RB to form a repressive multicomponent transcriptional complex that inhibits BRCA1 promoter transcription. This complex is disrupted by genotoxic stress, resulting in the displacement of BRCA1 protein from the BRCA1 promoter and subsequent upregulation of BRCA1 transcription. Cells depleted of BRCA1 respond by upregulating BRCA1 transcripts, whereas cells overexpressing BRCA1 respond by downregulating BRCA1 transcripts. Tandem chromatin immmunoprecipitation studies show that BRCA1 is regulated by a dynamic coregulatory complex containing BRCA1, E2F1, and Rb at the BRCA1 promoter that is disrupted by DNA-damaging agents to increase its transcription. These results define a novel transcriptional mechanism of autoregulated homeostasis of BRCA1 that selectively titrates its levels to maintain genome integrity in response to genotoxic insult.Fil: de Siervi, Adriana. National Cancer Institute; Estados Unidos. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: de Luca, Paola. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Byun, Jung S.. National Cancer Institute; Estados UnidosFil: Di, Li Jun. National Cancer Institute; Estados UnidosFil: Fufa, Temesgen. National Cancer Institute; Estados UnidosFil: Haggerty, Cynthia M.. National Cancer Institute; Estados UnidosFil: Vazquez, Elba Susana. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Moiola, Cristian Pablo. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Longo, Dan L.. National Institute on Aging; Estados UnidosFil: Gardner, Kevin. National Cancer Institute; Estados UnidosAmerican Association For Cancer Research2010-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/16581de Siervi, Adriana; de Luca, Paola; Byun, Jung S.; Di, Li Jun; Fufa, Temesgen; et al.; Transcriptional Autoregulation by BRCA1; American Association For Cancer Research; Cancer Research; 70; 2; 1-2010; 532-5420008-54721538-7445enginfo:eu-repo/semantics/altIdentifier/doi/10.1158/0008-5472.CAN-09-1477info:eu-repo/semantics/altIdentifier/url/http://cancerres.aacrjournals.org/content/70/2/532info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:03:19Zoai:ri.conicet.gov.ar:11336/16581instacron: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:34982025-10-22 11:03:19.3CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Transcriptional Autoregulation by BRCA1
title Transcriptional Autoregulation by BRCA1
spellingShingle Transcriptional Autoregulation by BRCA1
de Siervi, Adriana
Brca1
Transcripción
Daño en El Adn
Ciclo Celular
title_short Transcriptional Autoregulation by BRCA1
title_full Transcriptional Autoregulation by BRCA1
title_fullStr Transcriptional Autoregulation by BRCA1
title_full_unstemmed Transcriptional Autoregulation by BRCA1
title_sort Transcriptional Autoregulation by BRCA1
dc.creator.none.fl_str_mv de Siervi, Adriana
de Luca, Paola
Byun, Jung S.
Di, Li Jun
Fufa, Temesgen
Haggerty, Cynthia M.
Vazquez, Elba Susana
Moiola, Cristian Pablo
Longo, Dan L.
Gardner, Kevin
author de Siervi, Adriana
author_facet de Siervi, Adriana
de Luca, Paola
Byun, Jung S.
Di, Li Jun
Fufa, Temesgen
Haggerty, Cynthia M.
Vazquez, Elba Susana
Moiola, Cristian Pablo
Longo, Dan L.
Gardner, Kevin
author_role author
author2 de Luca, Paola
Byun, Jung S.
Di, Li Jun
Fufa, Temesgen
Haggerty, Cynthia M.
Vazquez, Elba Susana
Moiola, Cristian Pablo
Longo, Dan L.
Gardner, Kevin
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Brca1
Transcripción
Daño en El Adn
Ciclo Celular
topic Brca1
Transcripción
Daño en El Adn
Ciclo Celular
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The BRCA1 gene product plays numerous roles in regulating genome integrity. Its role in assembling supermolecular complexes in response to DNA damage has been extensively studied; however, much less is understood about its role as a transcriptional coregulator. Loss or mutation is associated with hereditary breast and ovarian cancers, whereas altered expression occurs frequently in sporadic forms of breast cancer, suggesting that the control of BRCA1 transcription might be important to tumorigenesis. Here, we provide evidence of a striking linkage between the roles for BRCA1 as a transcriptional coregulator with control of its expression via an autoregulatory transcriptional loop. BRCA1 assembles with complexes containing E2F-1 and RB to form a repressive multicomponent transcriptional complex that inhibits BRCA1 promoter transcription. This complex is disrupted by genotoxic stress, resulting in the displacement of BRCA1 protein from the BRCA1 promoter and subsequent upregulation of BRCA1 transcription. Cells depleted of BRCA1 respond by upregulating BRCA1 transcripts, whereas cells overexpressing BRCA1 respond by downregulating BRCA1 transcripts. Tandem chromatin immmunoprecipitation studies show that BRCA1 is regulated by a dynamic coregulatory complex containing BRCA1, E2F1, and Rb at the BRCA1 promoter that is disrupted by DNA-damaging agents to increase its transcription. These results define a novel transcriptional mechanism of autoregulated homeostasis of BRCA1 that selectively titrates its levels to maintain genome integrity in response to genotoxic insult.
Fil: de Siervi, Adriana. National Cancer Institute; Estados Unidos. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: de Luca, Paola. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Byun, Jung S.. National Cancer Institute; Estados Unidos
Fil: Di, Li Jun. National Cancer Institute; Estados Unidos
Fil: Fufa, Temesgen. National Cancer Institute; Estados Unidos
Fil: Haggerty, Cynthia M.. National Cancer Institute; Estados Unidos
Fil: Vazquez, Elba Susana. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Moiola, Cristian Pablo. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Longo, Dan L.. National Institute on Aging; Estados Unidos
Fil: Gardner, Kevin. National Cancer Institute; Estados Unidos
description The BRCA1 gene product plays numerous roles in regulating genome integrity. Its role in assembling supermolecular complexes in response to DNA damage has been extensively studied; however, much less is understood about its role as a transcriptional coregulator. Loss or mutation is associated with hereditary breast and ovarian cancers, whereas altered expression occurs frequently in sporadic forms of breast cancer, suggesting that the control of BRCA1 transcription might be important to tumorigenesis. Here, we provide evidence of a striking linkage between the roles for BRCA1 as a transcriptional coregulator with control of its expression via an autoregulatory transcriptional loop. BRCA1 assembles with complexes containing E2F-1 and RB to form a repressive multicomponent transcriptional complex that inhibits BRCA1 promoter transcription. This complex is disrupted by genotoxic stress, resulting in the displacement of BRCA1 protein from the BRCA1 promoter and subsequent upregulation of BRCA1 transcription. Cells depleted of BRCA1 respond by upregulating BRCA1 transcripts, whereas cells overexpressing BRCA1 respond by downregulating BRCA1 transcripts. Tandem chromatin immmunoprecipitation studies show that BRCA1 is regulated by a dynamic coregulatory complex containing BRCA1, E2F1, and Rb at the BRCA1 promoter that is disrupted by DNA-damaging agents to increase its transcription. These results define a novel transcriptional mechanism of autoregulated homeostasis of BRCA1 that selectively titrates its levels to maintain genome integrity in response to genotoxic insult.
publishDate 2010
dc.date.none.fl_str_mv 2010-01
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/11336/16581
de Siervi, Adriana; de Luca, Paola; Byun, Jung S.; Di, Li Jun; Fufa, Temesgen; et al.; Transcriptional Autoregulation by BRCA1; American Association For Cancer Research; Cancer Research; 70; 2; 1-2010; 532-542
0008-5472
1538-7445
url http://hdl.handle.net/11336/16581
identifier_str_mv de Siervi, Adriana; de Luca, Paola; Byun, Jung S.; Di, Li Jun; Fufa, Temesgen; et al.; Transcriptional Autoregulation by BRCA1; American Association For Cancer Research; Cancer Research; 70; 2; 1-2010; 532-542
0008-5472
1538-7445
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1158/0008-5472.CAN-09-1477
info:eu-repo/semantics/altIdentifier/url/http://cancerres.aacrjournals.org/content/70/2/532
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Association For Cancer Research
publisher.none.fl_str_mv American Association For Cancer Research
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
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score 12.982451

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