title: Hypoxia-induced down-regulation of BRCA1 expression by E2Fs.
abstract: Decreased BRCA1 expression in the absence of genetic mutation is observed frequently in sporadic cancers of the breast and other sites, although little is known regarding the mechanisms by which the expression of this gene can be repressed. Here, we show that activating and repressive E2Fs simultaneously bind the BRCA1 promoter at two adjacent E2F sites in vivo, and that hypoxia induces a dynamic redistribution of promoter occupancy by these factors resulting in the transcriptional repression of BRCA1 expression. Functionally, we show that hypoxia is associated with impaired homologous recombination, whereas the nonhomologous end-joining (NHEJ) repair pathway is unaffected under these conditions. Repression of BRCA1 expression by hypoxia represents an intriguing mechanism of functional BRCA1 inactivation in the absence of genetic mutation. We propose that hypoxia-induced decreases in BRCA1 expression and consequent suppression of homologous recombination may lead to genetic instability by shifting the balance between the high-fidelity homologous recombination pathway and the error-prone NHEJ pathway of DNA repair. Furthermore, these findings provide a novel link between E2Fs and the transcriptional response to hypoxia and provide insight into the mechanisms by which the tumor microenvironment can contribute to genetic instability in cancer.
authors.affiliation: Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Ranjit S
authors.initials: RS
authors.lastname: Bindra
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Gibson
authors.forename: Alice
authors.initials: A
authors.lastname: Meng
authors.forename: Ulrica
authors.initials: U
authors.lastname: Westermark
authors.forename: Maria
authors.initials: M
authors.lastname: Jasin
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Pierce
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bristow
authors.forename: Marie K
authors.initials: MK
authors.lastname: Classon
authors.forename: Peter M
authors.initials: PM
authors.lastname: Glazer
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia; D047369:Chromatin Immunoprecipitation; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D015536:Down-Regulation; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D019313:BRCA1 Protein; D050684:E2F Transcription Factors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D008156:Luciferases