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Papers In Press, published online ahead of print November 1, 2005
J. Biol. Chem, 10.1074/jbc.M509730200
Submitted on September 2, 2005
Revised on October 28, 2005
Accepted on October 31, 2005

Functional human mitochondrial DNA polymerase gamma forms a heterotrimer

Elena Yakubovskaya, Zhixin Chen, Jose A. Carrodeguas, Caroline Kisker, and Daniel F. Bogenhagen

Pharmacological Sciences, SUNY Stony Brook, Stony Brook, NY 11794-8651

Corresponding Author: dan{at}pharm.sunysb.edu

Mitochondrial DNA polymerase gamma (polgamma ) is responsible for replication and repair of mtDNA and is mutated in individuals with genetic disorders such as chronic external opthalmoplegia and Alpers syndrome. Polgamma 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 polgamma catalytic subunit with both the wild-type accessory factor, polgamma 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 show that the functional human holoenzyme contains two subunits of the processivity factor and one catalytic subunit, thereby forming a heterotrimer. The structure of polgamma . seems to be variable, ranging from a single catalytic subunit in yeast to a heterodimer in Drosophila and a heterotrimer in mammals.


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