In its broadest sense, this research addresses the metabolism of nucleotides and nucleic acids. The approach involves the characterization of enzymes which catalyze reactions at the nucleotide level, at stages during nucleic acid synthesis and replication, and at the completed nucleic acid molecules themselves. A fertile ground for this study has been, and will continue to be, the study of mutator genes which cause hundred- to thousand-fold increases in spontaneous mutation rates. Experience has shown that these mutator genes code for defective enzymes, each catalyzing one of the steps required for the faithful (error-free) synthesis of DNA, or for its post-replication repair. These studies not only help elucidate the physiological role of the series of enzymes involved in nucleic acid synthesis and modification, but they invariably lead to the discovery of new proteins essential to the process. An important ancillary feature of the work is its application to the broader area of protein-nucleic acid recognition and interactions. The specific projects include: a - characterization of the MutT protein which prevents a thousand-fold increase in spontaneous mutations during DNA replication. b - elucidation of the unusual specificity of a deoxynucleotide kinase c - investigation of a newly discovered, broadly distributed, signature sequence of amino acids, which represents a novel nucleotide binding site and catalytic center for the hydrolysis of nucleotide pyrophosphate linkages. Recent clinical studies by others have pointed up the important role of DNA replication and repair enzymes in human disease. Human homologues of several bacterial genes involved in maintaining DNA fidelity are now being implicated in the etiology of human cancer.
