MECHANISMS OF P53 MUTAGENESIS

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Our overall goal is to dissect the molecular components of somatic mutagenesis and incorporate these into a sound rationale for the molecular epidemiology of cancer. Our specific goal is to determine the effect of suspected environmental and endogenous mutagens on the molecular epidemiology of p53 mutations. Using a variety of mutagens, we will map patterns of mutagenesis along each nucleotide position of the p53 gene exons 5-9. The patterns of mutagenesis metrics involve base positions which are heavily damaged or slowly repaired and occur predominantly in those patients who are least proficient at repairing the suspected class of lesions. We will search for a correlation between a mutagenesis metric which forms the pattern and components of each mutagen's mutational signature in the p53 tumor mutation data. Our procedural theme for relating the components of mutageneses involves having four projects concentrating on mapping various molecular phenomena along only one gene, p53, and to thoroughly understand for the first time how these molecular phenomena are interrelated in their determination of mutation frequency. The theme of operations is to facilitate this technology so that mapping of molecular properties will get accomplished. The four projects exploring the mutagenesis mechanisms are: 1) Mechanisms of Ultraviolet Light-Induced p53 Mutations; 2) Mechanisms of Chemical Carcinogen-Induced p53 Mutations; 3) Mechanisms of Oxidative Damage- Induced p53 Mutations; and 4) Base Excision Repair and Alkylating Chemotherapeutic Agent-Induced p53 Damage. The four experimental projects are supported by three cores. The first core will be coordinating and sharing common reagents and for developing and automating the ligation-mediated PCR, the second is for tissue culture, and the third is for administration of the program.