title: Transcriptional autoregulation by BRCA1.
abstract: 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.
authors.affiliation: Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, Bethesda, Maryland 20892-5065, USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: De Siervi
authors.forename: Paola
authors.initials: P
authors.lastname: De Luca
authors.forename: Jung S
authors.initials: JS
authors.lastname: Byun
authors.forename: Li Jun
authors.initials: LJ
authors.lastname: Di
authors.forename: Temesgen
authors.initials: T
authors.lastname: Fufa
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Haggerty
authors.forename: Elba
authors.initials: E
authors.lastname: Vazquez
authors.forename: Cristian
authors.initials: C
authors.lastname: Moiola
authors.forename: Dan L
authors.initials: DL
authors.lastname: Longo
authors.forename: Kevin
authors.initials: K
authors.lastname: Gardner
mesh_terms: D019313:BRCA1 Protein / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D006706:Homeostasis; D006801:Humans; D019169:Jurkat Cells; D008297:Male; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human