DNA damage is an Initiating step in cancer etiology. This renewal focuses upon understanding the chemistry and biology of various types of DNA damage, which are directly or indirectly related to various sources of cellular oxidative stress and inflammation, and significant with respect to cancer etiology. An ancillary theme is that once formed, these adducts often undergo further chemistry, which may be reversible, e.g., in the case of malondialdehyde (MDA), 5,6-dihydroxy-dihydro-2'-thymlne or Tg, or Irreversible, in the case of aflatoxin B{1} (AFB{1}). Indeed, some of the secondary lesions; e.g., DNA cross-links or N7-dG FAPY lesions, are more deleterious than are the initial lesions. Their chemistry and biological processing depend upon whether the DNA exists as a duplex or is single-stranded, and depends upon the sequence and identity of the complementary nucleotide. If the aims of this application are successful, structure-activity relationships delineating the complex chemistry of these lesions, and the resulting structural alterations to DNA, and their interactions with DNA processing enzymes will be obtained, which will translate into an understanding as to how their respective chemistry modulates their biological processing; our work may also facilitate the identification of potential new targets for chemotherapeutic intervention in human disease.
The goal is to understand mechanisms by which exposures to malondialdehyde, aflatoxin B{1} and specific oxidative damages to thymine and guanine contribute to the etiology of cancer. Each is directly or indirectly related to cellular oxidative stress and inflammation. Malondialdehyde, aflatoxin B{1} and thymine glycol DNA adducts also undergo transformations once formed, e.g., unmasking new chemical functionality that may differentially modulate repair and replication, or facilitate secondary chemistry such as formation of interstrand cross-links. Understanding the structure-activity relationships delineating the chemistry of these lesions, their structural alterations to DNA, and interactions with DNA processing enzymes will translate into an understanding as to how their chemistry modulates biological processing: our work may also facilitate the identification of targets for chemotherapeutic intervention in human disease.
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