Human Molecular Genetics Advance Access published online on December 20, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi454
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1 Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710
* To whom correspondence should be addressed. A number of nuclear mutations have been identified in a variety of mitochondrial diseases including progressive external ophthalmoplegia (PEO), Alpers syndrome, and other neuromuscular and oxidative phosphorylation defects. More than fifty mutations have been identified in POLG, which encodes the human mitochondrial DNA polymerase
Received October 28, 2005
Revised December 9, 2005
Accepted December 9, 2005
Article
Mitochondrial and nuclear DNA defects in Saccharomyces cerevisiae with mutations in DNA polymerase
Gregory R. Stuart 1,
Janine H. Santos 2,
Micheline K. Strand 2,
Bennett Van Houten 2,
and
William C. Copeland 2 *
associated with progressive external ophthalmoplegia
2 Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709
William C. Copeland, E-mail: copelan1{at}niehs.nih.gov
Abstract 
, in PEO and Alpers patients. To rapidly characterize the effects of these mutations, we have developed a versatile system that enables the consequences of homologous mutations, introduced in situ into the yeast mitochondrial DNA polymerase gene MIP1, to be evaluated in vivo in haploid and diploid cells. Overall, distinct phenotypes for expression of each of the mip1-PEO mutations were observed, including respiration-defective cells with decreased viability, dominant-negative mutant polymerases, elevated levels of mitochondrial and nuclear DNA damage, and chromosomal mutations. Mutations in the polymerase domain caused the most severe phenotype accompanied by loss of mitochondrial DNA and cell viability, while the mutation in the exonuclease domain showed mild dominance with loss of mitochondrial DNA. Interestingly, the linker region mutation caused elevated mitochondrial and nuclear DNA damage. The cellular processes contributing to these observations in the mutant yeast cells are potentially relevant to understanding the pathologies observed in human mitochondrial disease patients.
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