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Papers In Press, published online ahead of print March 15, 2002
J. Biol. Chem, 10.1074/jbc.C200100200
Submitted on February 15, 2002
Revised on March 11, 2002
Accepted on March 14, 2002

Active site mutation in DNA polymerase gamma associated with progressive external ophthalmoplegia causes error-prone DNA synthesis

Mikhail V. Ponamarev, Matthew J. Longley, Dinh Nguyen, Thomas A. Kunkel, and William C. Copeland

Laboratory of Molecular Genetics, NIEHS, Research Triangle Park, NC 27709

Corresponding Author: copelan1{at}niehs.nih.gov

Progressive external ophthalmoplegia (PEO) is a heritable mitochondrial disorder characterized by the accumulation of multiple point mutations and large deletions in mitochondrial DNA (mtDNA). Autosomal dominant PEO was recently shown to co-segregate with a heterozygous Y955C mutation in the human gene encoding the sole mitochondrial DNA polymerase, DNA polymerase gamma . Since Y955 is a highly conserved residue critical for nucleotide recognition among Family A DNA polymerases, we analyzed the effects of the Y955C mutation on the kinetics and fidelity of DNA synthesis by the purified human mutant polymerase in complex with its accessory subunit. The Y955C enzyme retains a wild-type catalytic rate (kcat) but suffers a 45-fold decrease in apparent binding affinity for the incoming nucleoside triphosphate (KM). The Y955C derivative is twofold less accurate for base-pair substitutions than wild-type pol gamma despite the action of intrinsic exonucleolytic proofreading. The full mutator effect of the Y955C substitution was revealed by genetic inactivation of the exonuclease, and error rates for certain mismatches were elevated by 10- to 100-fold. The error prone DNA synthesis observed for the Y955C pol gamma is consistent with the accumulation of mtDNA mutations in patients with PEO.


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