DNA repair is a universal cellular mechanism to maintain genome integrity. Defects in DNA repair are associated with a variety of human diseases including cancer. Nitrosative stress is a subclass of oxidative stress caused by exposure to nitric oxide and its derivatives, collectively known as reactive nitrogen species (RNS). Nitrogen oxides (NOx) in the environment or RNS produced from endogenous sources can cause deamination in DNA bases. Our long-term research objectives are to understand deaminated DNA damage and repair and its potential link to human disease. Guanine base is converted to xanthine by oxidative deamination, which can be a source of mutation, in particular in tissues that are exposed to the outside environment, such as lungs. Mammalian alkyladenine DNA glycosylase (Aag) has been identified as xanthine DNA glycosylase (XDG). The central hypothesis is that mammalian systems are equipped with multiple repair systems to remove DNA base damage caused by guanine deamination. This hypothesis is based on our experimental observation of multiple xanthine DNA glycosylase activities in lung tissues of Aag knockout mice. In particular, one of the activity peaks is unaccounted for by any known mammalian repair enzymes. The short-term goal of this proposal is to identify this previously unknown DNA repair enzyme involved in removal of xanthine base damage in mammalian systems. Biochemical fractionation will be carried out in mammalian tissues to isolate the repair enzyme, and then its molecular nature will be identified by mass spectrometric analysis. Identification of this new class of mammalian deamination DNA glycosylase will break new ground in understanding human DNA repair, as it will open broad avenues for investigation of: (1) its biochemical mechanism of enzymatic action;(2) its regulation of gene expression and response to nitrosative stress;(3) its relationship to mutagenicity and genome stability;and (4) its potential link with human diseases, in particular cancer.
Exposure to highly reactive nitrogen radicals can cause damage to DNA. DNA repair is an important mechanism for removing damage caused by these radicals. Defects in DNA repair pathways are associated with genome instability and carcinogenesis. Study of repair caused by DNA deamination is essential for understanding the potential link between DNA repair and human diseases such as cancer.
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