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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/16581
Ver los metadatos del registro completo
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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 Técnicas2025-09-29T09:35:17Zoai: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:34982025-09-29 09:35:17.701CONICET 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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1844613098071130112 |
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13.070432 |