Lawrence A. Loeb, M.D., Ph.D.
University of Washington

Aging in Mutator and Antimutator Mice.

Accurate copying of DNA in cells is carried out by DNA polymerases. These enzymes polymerize nulceotides that are complementary to the nucleotides in the cellular DNA template, yielding daughter DNA molecules that preserve the nucleotide sequence of the parental molecules. Errors in this process, if not repaired, result in mutations. Mutations in DNA polymerases themselves can lead to inaccurate copying of template DNA and to a general mutator phenotype. We are now in a position to determine if alterations in DNA polymerases can cause mutations throughout the genomes of animal cells, and whether these mutations accumulate in somatic cells during aging. We propose to create a series of mice in which a wild type DNA polymerase(s) is replaced by a mutant DNA polymerase that exhibits either a decrease or an increase in fidelity. The construction of such a series of mice should allow us to determine the relationship of the fidelity of DNA synthesis to the aging phenotype, and to document an association of mutations produced by DNA polymerases with the pathologies associated with aging.

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