Thomas A. Kunkel

Research examines the fidelity of DNA synthesis. Developed comprehensive assay to study the fidelity of DNA synthesis and used it to demonstrate that nucleotide selectivity can vary over a million-fold range. Revealed one novel mechanism for generating base substitutions and a second for generating base deletions. Structural studies advanced understanding of the catalytic cycle for DNA polymerization and the structural basis of DNA strand slippage and nucleotide misinsertion. Reported that the AIDS virus replicase is highly inaccurate, explaining the emergence of drug-resistant virus. Discovered the proofreading activity of the mitochondrial DNA replicase, defects in which are associated with mitochondrial diseases and aging. Elucidated contribution of proofreading by eukaryotic nuclear replicases to DNA synthesis fidelity and genome stability, defects which are associated with cancer. Recently discovered that the leading and lagging strand replicases insert surprisingly large numbers of rNTPs into DNA during replication and that failure to repair rNMPs in DNA results in genome instability. Provided recent evidence for the division of labor among three major replicases in replication of eukaryotic nuclear DNA.