A mechanistic view of human mitochondrial DNA polymerase gamma: providing insight into drug toxicity and mitochondrial disease.
Mitochondrial DNA polymerase gamma (Pol gamma) is the sole polymerase responsible for replication of the mitochondrial genome. The study of human Pol gamma is of key importance to clinically relevant issues such as nucleoside analog toxicity and mitochondrial disorders such as progressive external ophthalmoplegia. The development of a recombinant form of the human Pol gamma holoenzyme provided an essential tool in understanding the mechanism of these clinically relevant phenomena using kinetic methodologies. This review will provide a brief history on the discovery and characterization of human mitochondrial DNA polymerase gamma, focusing on kinetic analyses of the polymerase and mechanistic data illustrating structure-function relationships to explain drug toxicity and mitochondrial disease.
Bailey
Christopher M
CM
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
Anderson
Karen S
KS
D019380:Anti-HIV Agents / Q000009:adverse effects*; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology*; D028361:Mitochondrial Diseases / Q000139:chemically induced*
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase