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(PP288) Stress-induced regulation of BRCA1 expression by E2Fs.
Bindra, Ranjit*,1, 2, Gibson, Shannon1, 7, Meng, Alice5, 6, Jasin, Maria 3, Pierce, Andrew4, Bristow, Robert5, 6, Classon, Marie7, Glazer, Peter1, 8, 1 Department of Therapeutic Radiology, New Haven, CT, USA2 Department of Experimental Pathology, New Haven, CT, USA7 MGH Cancer Center, Charlestown, MA, USA5 Ontario Cancer Institute, Toronto, Ontario, Canada6 Department of Medical Biophysics, Toronto, Ontario, Canada3 Molecular Biology Program, New York, NY, USA4 Department of Microbiology, Immunology and Molecular Genetics, Lexington, KY, USA8 Department of Genetics, New Haven, CT, USA
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. The adjacent and oppositely transcribed NBR2 gene is unaffected under these conditions, suggesting unidirectional repression by hypoxia in the context of this bidirectional promoter. These data suggest a novel mechanism of functional BRCA1 inactivation in the absence of genetic mutation, and they implicate E2Fs in the transcriptional response to key microenvironmental stresses such as hypoxia.
Key words: Hypoxia, BRCA1, Tumor Microenvironment, DNA repair
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