Artículo
Transcriptional Autoregulation by BRCA1
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
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Fecha de publicación:
01/2010
Editorial:
American Association For Cancer Research
Revista:
Cancer Research
ISSN:
0008-5472
e-ISSN:
1538-7445
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
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.
Palabras clave:
Brca1
,
Transcripción
,
Daño en El Adn
,
Ciclo Celular
Archivos asociados
Licencia
Identificadores
Colecciones
Articulos(OCA CIUDAD UNIVERSITARIA)
Articulos de OFICINA DE COORDINACION ADMINISTRATIVA CIUDAD UNIVERSITARIA
Articulos de OFICINA DE COORDINACION ADMINISTRATIVA CIUDAD UNIVERSITARIA
Citación
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
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