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Originally published In Press as doi:10.1074/jbc.C200100200 on March 15, 2002

J. Biol. Chem., Vol. 277, Issue 18, 15225-15228, May 3, 2002
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ACCELERATED PUBLICATION
Active Site Mutation in DNA Polymerase gamma  Associated with Progressive External Ophthalmoplegia Causes Error-prone DNA Synthesis*

Mikhail V. PonamarevDagger , Matthew J. LongleyDagger , Dinh NguyenDagger , Thomas A. KunkelDagger §, and William C. CopelandDagger

From the Dagger  Laboratory of Molecular Genetics and § Laboratory of Structural Biology, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709

Progressive external ophthalmoplegia (PEO) is a heritable mitochondrial disorder characterized by the accumulation of multiple point mutations and large deletions in 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  (pol gamma ). Since Tyr-955 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 2-fold 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 10-100-fold. The error-prone DNA synthesis observed for the Y955C pol gamma  is consistent with the accumulation of mtDNA mutations in patients with PEO.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Laboratory of Molecular Genetics, NIEHS, National Institutes of Health, P.O. Box 12233, Research Triangle Park, NC 27709. Tel.: 919-541-4792; Fax: 919-541-7613; E-mail: copelan1@niehs.nih.gov.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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