Regulation of BER Gene Expression by Folate Deficiency

描述(申请人提供)：本研究的目标是揭示碱基切除修复活性改变影响癌症易感性的分子机制(S)。本研究的目的是阐明叶酸缺乏导致DNA修复缺陷表型的机制。由于DNA修复缺陷会增加癌症的易感性，因此有理由认为，确定叶酸缺乏抑制DNA修复的潜在机制将有助于了解叶酸缺乏增加癌症风险的潜在机制。我的假设是，叶酸缺乏降低了对DNA损伤的耐受性，并通过改变(-ol)的调节而导致功能性BER缺陷。具体目标1：确定饮食中缺乏叶酸会导致功能性BER缺乏。具体目标2：确定饮食中叶酸的缺乏会阻止致癌物暴露时(-Poll)的上调，从而阻止BER对氧化损伤的反应。具体目标3：建立膳食叶酸缺乏改变(-ol)调节的机制。当叶酸缺乏时，BER对DNA损伤的反应丧失，将建立一种机制，通过这种机制，饮食可以改变对环境暴露的敏感性。

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.