Folate deficiency regulates expression of DNA polymerase β in response to oxidative stress.
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.
Department of Nutrition and Food Science, Science College of Liberal Arts and Sciences, Wayne State University, Detroit, MI 48202, USA.
Archana
A
Unnikrishnan
Tom M
TM
Prychitko
Hiral V
HV
Patel
Mahbuba E
ME
Chowdhury
Amanda B
AB
Pilling
Lisa F
LF
Ventrella-Lucente
Erin V
EV
Papakonstantinou
Diane C
DC
Cabelof
Ahmad R
AR
Heydari
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology; D002467:Cell Nucleus / Q000235:genetics; D002478:Cells, Cultured; D018899:CpG Islands / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D018983:DNA Footprinting; D019175:DNA Methylation; D019951:DNA Polymerase beta / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D057890:Epigenomics; D005492:Folic Acid / Q000378:metabolism; D005494:Folic Acid Deficiency / Q000235:genetics*; D005786:Gene Expression Regulation; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic / Q000235:genetics
D000080242:8-Hydroxy-2'-Deoxyguanosine; D005492:Folic Acid; D019951:DNA Polymerase beta; D003849:Deoxyguanosine