MECHANISMS OF DNA POLYMERASE BETA IN DNA FIDELITY

Yale University, New Haven CT

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Abstract

DNA polymerase beta (pol beta) is an essential component of the base excision repair pathway, which removes about 10,000 DNA lesions per cell per day. The significance of pol beta in human disease is apparent, as mutations of pol beta have been found in patients with bladder, colon, and prostate cancers. A possible explanation for the link is that the mutations produce abnormal enzyme function that generates a pol beta mutator phenotype. This form of the enzyme may insert incorrect deoxynucleotide triphosphates (dNTP) with equal or greater efficiency as correct dNTP substrates. Thus, elucidating the mechanism of pol beta in DNA fidelity may provide insights into the molecular events that lead to mutagenesis and tumor cell development. Specific aims of the project include: 1) to identify amino acid residues of pol beta that influence DNA fidelity; 2) to determine the function of altered amino acid residues present in pol beta mutator mutants; 3) to determine the types of chemical interactions that govern DNA fidelity. The specific goals of the project are consistent of determining the mechanisms of how polymerases accurately synthesize DNA. These findings may yield information about the molecular events that give rise to increased mutagenesis.