Christopher K. Mathews

Research in the Mathews laboratory is concerned with the enzymology and metabolism of DNA precursors, the four deoxyribonucleoside triphosphates, or dNTPs. Part of the interest relates to understanding how dNTP biosynthesis is coordinated with DNA replication in the cell, ensuring that nucleotides are provided at sufficient rates to drive rapidly moving replication forks and ensuring in turn that DNA replication is properly coordinated with the cell's growth and division cycle. Additional interest derives from the fact that enzymes of dNTP synthesis are targets for anticancer, antiviral, and antimicrobial chemotherapy, and fundamental understanding of the enzymes and their regulation may reveal more effective ways to use antimetabolites.

Current work in the Mathews laboratory focuses upon two main questions: (1) How do perturbations of dNTP metabolism affect replication fidelity and mutagenesis? (2) What are the metabolic and cellular sources for dNTPs used in eukaryotic mitochondrial DNA replication?

Specific questions receiving experimental attention include: (1) Reactive oxygen species are mutagenic, and we are evaluating the hypothesis that much of the genetic damage results from oxidation of nucleotides followed by their enzymatic incorporation into DNA, leading to mutagenic DNA base pairs. (2) We have found that dNTP pools within mammalian mitochondria are highly asymmetric, and that the unbalanced intramitochondrial dNTP concentrations may be partly responsible for the high rate of mitochondrial as compared to nuclear gene mutagenesis. We are trying to understand the enzymatic basis for the large imbalances in mitochondrial dNTP pools. (3) In principle mitochondrial dNTP pools could arise either through synthesis within the mitochondrion from ribonucleoides, through active transport of nucleoside triphosphates from the cytosol, or from diffusion of deoxyribonucleosides into the mitochondrion, followed by their phosphorylation to dNTPs within the organelle. We are trying to evaluate the significance of each pathway and to learn whether mitochondria from different tissues vary in their relative utilization of each pathway. Much of the data being generated will be furnished to a collaborator, who is using computer simulation to model mitochondrial dNTP synthesis, learning thereby how different disease states are derived from perturbations of mitochondrial nucleotide metabolism.

Note. Dr. Mathews' status as "Professor Emeritus" derives from the fact that he has retired from the OSU faculty. Consequently, he is no longer able to accept new Ph.D. students and serve as major professor, although he is available to serve on graduate student committees or to provide assistance as needed in their research in other laboratories.