1. Folate deficiency regulates expression of DNA polymerase β in response to oxidative stress.
- Author
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Unnikrishnan A, Prychitko TM, Patel HV, Chowdhury ME, Pilling AB, Ventrella-Lucente LF, Papakonstantinou EV, Cabelof DC, and Heydari AR
- Subjects
- 8-Hydroxy-2'-Deoxyguanosine, Animals, Base Sequence, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular pathology, Cell Nucleus genetics, Cells, Cultured, CpG Islands genetics, DNA Damage genetics, DNA Footprinting, DNA Repair genetics, Deoxyguanosine analogs & derivatives, Deoxyguanosine metabolism, Electrophoretic Mobility Shift Assay, Folic Acid metabolism, Liver cytology, Liver metabolism, Liver Neoplasms, Experimental genetics, Liver Neoplasms, Experimental pathology, Male, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Promoter Regions, Genetic genetics, DNA Methylation, DNA Polymerase beta genetics, Epigenomics, Folic Acid Deficiency genetics, Gene Expression Regulation, Oxidative Stress
- Abstract
Folate deficiency has been shown to influence carcinogenesis by creating an imbalance in the base excision repair (BER) pathway, affecting BER homeostasis. The inability to mount a BER response to oxidative stress in a folate-deficient environment results in the accumulation of DNA repair intermediates, i.e., DNA strand breaks. Our data indicate that upregulation of β-pol expression in response to oxidative stress is inhibited by folate deficiency at the level of gene expression. Alteration in the expression of β-pol in a folate-deficient environment is not due to epigenetic changes in the core promoter of the β-pol gene, i.e., the CpG islands within the β-pol promoter remain unmethylated in the presence or absence of folate. However, the promoter analysis studies show a differential binding of regulatory factors to the -36 to -7 region (the folic acid-response region, FARR) within the core promoter of β-pol. Moreover, we observe a tight correlation between the level of binding of regulatory factors with the FARR and inhibition of β-pol expression. Based on these findings, we propose that folate deficiency results in an upregulation/stability of negative regulatory factors interacting with FARR, repressing the upregulation of the β-pol gene in response to oxidative stress., (Copyright © 2010 Elsevier Inc. All rights reserved.)
- Published
- 2011
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