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Chair(s): Spitz, Douglas
(SY017) Chronic hypoxia/preferfusion induced Oxidative Stress activates methyltransferase activity to induce expression of the BAG pro-survival gene family via the testis specific insulator protein BORIS.
Gius, David*,1, 1 Molecular Radiation Oncology Section, Radiation Oncology Branch, Bethesda, MD, USA
ABSTRACT- Our research group has shown that: (1) agents that induce oxidative stress (H2O2, IR, and hypoxia) activate DNMT; (2) hypermethylation activates as many genes as are silenced; and (3) the CTCF binding sites are critical for this regulation. This was done using agents that inhibit either DNMT activity (5-aza-CdR) or chromatin compaction (TSA), somatic DNMT knockout cell lines with deleted DNMT1, DNMT3B, or both genes, and DNMT1 and DNMT3B over expressing cell lines. These results suggest a different paradigm for how DNMT regulates gene expression and suggests that DNMT may both activate and represses gene expression. This includes all four of the pro-survival BAG genes. We show that the two insulator proteins, CTCF and BORIS, compete for binding to the CTCF DNA-binding sites in the promoters of BAG genes and this alternating binding subsequently regulates expression of these genes and likely specific aspects of the epigenome. Thus, we suggest a model whereby oxidative stress, from either anti-cancer agents or the tumor microenvironment, induces chronic oxidative stress inducing DNMT activity to increase the gene expression of pro-survival genes that allow tumor cells to evade cytotoxicity.
Key words: oxidative stress, methyltransferase genes, hypoxia, BAG Family Genes
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