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J. Biol. Chem., Vol. 281, Issue 1, 374-382, January 6, 2006

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Functional Human Mitochondrial DNA Polymerase Forms a Heterotrimer^*

Elena Yakubovskaya1, Zhixin Chen1, José A. Carrodeguas2, Caroline Kisker, and Daniel F. Bogenhagen3

From the Department of Pharmacological Sciences and Center for Structural Biology, State University of New York, Stony Brook, New York 11794-8651

Mitochondrial DNA polymerase (pol ) is responsible for replication and repair of mtDNA and is mutated in individuals with genetic disorders such as chronic external ophthalmoplegia and Alpers syndrome. pol is also an adventitious target for toxic side effects of several antiviral compounds, and mutation of its proofreading exonuclease leads to accelerated aging in mouse models. We have used a variety of physical and functional approaches to study the interaction of the human pol catalytic subunit with both the wild-type accessory factor, pol B, and a deletion derivative that is unable to dimerize and consequently is impaired in its ability to stimulate processive DNA synthesis. Our studies clearly showed that the functional human holoenzyme contains two subunits of the processivity factor and one catalytic subunit, thereby forming a heterotrimer. The structure of pol seems to be variable, ranging from a single catalytic subunit in yeast to a heterodimer in Drosophila and a heterotrimer in mammals.

Received for publication, September 2, 2005 , and in revised form, October 28, 2005.

^* This work was supported by National Institutes of Health Grant R01-GM029681. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² Present address: Laboratory of Molecular Toxicology, Dept. of Pathological Anatomy, Legal and Forensic Medicine and Toxicology, University of Zaragoza, Zaragoza, Spain.

³ To whom correspondence should be addressed: Dept. of Pharmacological Sciences, State University of New York, Stony Brook, NY 11794-8651. Tel.: 631-444-3068; Fax: 631-444-3218; E-mail: dan{at}pharm.sunysb.edu.

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