Folate deficiency regulates expression of DNA polymerase β in response to oxidative stress

Abstract

Folate deficiency has been shown to influence carcinogenesis by creating an imbalance in the base excision repair (BER) pathway impacting 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 in β-pol expression in response to oxidative stress is inhibited by folate deficiency at the level of gene expression. Alteration in 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 and/or absence of folate. However, the promoter analysis studies show a differential binding of regulatory factor(s) 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 factor(s) 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 factor(s) interacting with FARR, repressing the upregulation of the β-pol gene in response to oxidative stress.

Maternal folate depletion and high‐fat feeding from weaning affects DNA methylation and DNA repair in brain of adult offspring

“…With the exception of Ogg1 that was hypermethylated (at CpG11 and averaged across all CpG sites) in the subcortical regions and hypermethylation of CpG site 7 in Xrcc1 in the hippocampus, the methylation levels of the other BER genes investigated here were not significantly affected by the maternal low‐folate diet (Table 3). This observation is supported by previous findings that folate depletion had no effect on the methylation of promoter regions of BER genes (35). However, it is possible that we did not investigate methylation of the gene domains that are most susceptible to environmental exposures such as folate depletion.…”

The excitatory neurotransmitter glutamate stimulates DNA repair to increase neuronal resiliency

“…DNA polymerase β is also moderately elevated after glutamate exposure (Yang et al 2010). This trend correlates with previous reports that DNA polymerase β is induced in a protective response to genotoxic stress (Cabelof et al 2002; Cabelof et al 2003; Sykora and Snow 2008; Unnikrishnan et al 2010). It is apparent that neurons are able to efficiently regulate BER; however, it remains to be seen what affect the decline in BER capacity attributed to aging may have on glutamate genotoxicity.…”

Biological role of 8-oxo-2'-deoxyguanosine

“…В этот период компенсации про-исходит резкий рост активности целого ряда анти-оксидантных и репаративных ферментов [20,21]. Правда, в большинстве случаев неочевидно, сам ли 8-oxo-dG вызывает усиление экспрессии генов этих ферментов, либо это производится иными продук-тами окислительных реакций.…”