Repression of RAD51 gene expression by E2F4/p130 complexes in hypoxia.
We and others have shown that the dysregulation of DNA repair pathways can contribute to the phenomenon of hypoxia-induced genetic instability within the tumor microenvironment. Several studies have revealed that the recombinational repair genes, RAD51 and BRCA1, and the DNA mismatch repair genes, MLH1 and MSH2, are decreased in expression in response to hypoxic stress, prompting interest in elucidating the mechanistic basis for these responses. Here we report that the downregulation of RAD51 by hypoxia is specifically mediated by repressive E2F4/p130 complexes that bind to a single E2F site in the proximal promoter of the gene. Intriguingly, this E2F site is conserved in the promoter of the BRCA1 gene, which is also regulated by a similar mechanism in hypoxia. Mechanistically, we have found that hypoxia induces substantial p130 dephosphorylation and nuclear accumulation, leading to the formation of E2F4/p130 complexes and increased occupancy of E2F4 and p130 at the RAD51 and BRCA1 promoters. These findings reveal a coordinated transcriptional program mediated by the formation of repressive E2F4/p130 complexes that represents an integral response to hypoxic stress. In addition, this co-regulation of key factors within the homology-dependent DNA repair pathway provides a further basis for understanding genetic instability in tumors and may guide the design of new therapeutic strategies for cancer.
Bindra
R S
RS
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520-8040, USA.
Glazer
P M
PM
D000595:Amino Acid Sequence; D019313:BRCA1 Protein / Q000235:genetics; D001665:Binding Sites; D045744:Cell Line, Tumor; D050719:Crk-Associated Substrate Protein / Q000378:metabolism*; D004260:DNA Repair / Q000235:genetics; D015536:Down-Regulation; D050704:E2F4 Transcription Factor / Q000378:metabolism*; D005786:Gene Expression Regulation; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051135:Rad51 Recombinase / Q000235:genetics*
C493841:BCAR1 protein, human; D019313:BRCA1 Protein; D050719:Crk-Associated Substrate Protein; D050704:E2F4 Transcription Factor; C493762:E2F4 protein, human; C495153:RAD51 protein, human; D051135:Rad51 Recombinase