Regulation of BER Gene Expression by Folate Deficiency

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DESCRIPTION (provided by applicant): The goal of this research is to reveal the molecular mechanism(s) by which alterations in base excision repair (BER) activity affect cancer susceptibility. The objective of this research is to elucidate the mechanism by which folate deficiency results in a phenotype of DNA repair deficiency. Because DNA repair deficiency increases susceptibility to cancer, it is reasonable to suggest that identification of the underlying mechanisms by which folate deficiency inhibits DNA repair will be informative with respect to the underlying mechanisms by which folate deficiency increases cancer risk. My hypothesis is that folate deficiency reduces tolerance to DNA damage and induces a functional BER deficiency by altering the regulation of (- pol. Specific Aim 1: Establish that a lack of dietary folate results in a functional BER deficiency. Specific Aim 2: Establish that a lack of dietary folate prevents upregulation of (-pol in response to carcinogen exposure, blocking the BER response to oxidative damage. Specific Aim 3: Establish the mechanism by which a lack of dietary folate alters regulation of (-pol. The loss of the BER response to DNA damage when folate is deficient would establish a mechanism by which diet can alter susceptibility to environmental exposure.