Hypoxia-Induced Down-regulation of BRCA1 Expression by E2Fs
- 15 December 2005
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 65 (24), 11597-11604
- https://doi.org/10.1158/0008-5472.can-05-2119
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. (Cancer Res 2005; 65(24): 11597-604)Keywords
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This publication has 47 references indexed in Scilit:
- Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategyNature, 2005
- Adaptive Myogenesis under HypoxiaMolecular and Cellular Biology, 2005
- Genetic instability and the tumor microenvironment: towards the concept of microenvironment-induced mutagenesisMutation Research - Reviews in Mutation Research, 2005
- Defective DNA Strand Break Repair after DNA Damage in Prostate Cancer CellsCancer Research, 2004
- E2Fs link the control of G1/S and G2/M transcriptionThe EMBO Journal, 2004
- The emerging role of E2F-1 in the DNA damage response and checkpoint controlDNA Repair, 2004
- Expression of E2F-4 in invasive breast carcinomas is associated with poor prognosisThe Journal of Pathology, 2004
- E2F6 Negatively Regulates BRCA1 in Human Cancer Cells without Methylation of Histone H3 on Lysine 9Published by Elsevier BV ,2003
- ATR/ATM Targets Are Phosphorylated by ATR in Response to Hypoxia and ATM in Response to ReoxygenationPublished by Elsevier BV ,2003
- BRCA1 Facilitates Microhomology-mediated End Joining of DNA Double Strand BreaksPublished by Elsevier BV ,2002