Mitochondrial DNA replication and disease: insights from DNA polymerase γ mutations
- 8 October 2010
- journal article
- review article
- Published by Springer Science and Business Media LLC in Cellular and Molecular Life Sciences
- Vol. 68 (2), 219-233
- https://doi.org/10.1007/s00018-010-0530-4
Abstract
DNA polymerase γ (pol γ), encoded by POLG, is responsible for replicating human mitochondrial DNA. About 150 mutations in the human POLG have been identified in patients with mitochondrial diseases such as Alpers syndrome, progressive external ophthalmoplegia, and ataxia-neuropathy syndromes. Because many of the mutations are described in single citations with no genotypic family history, it is important to ascertain which mutations cause or contribute to mitochondrial disease. The vast majority of data about POLG mutations has been generated from biochemical characterizations of recombinant pol γ. However, recently, the study of mitochondrial dysfunction in Saccharomyces cerevisiae and mouse models provides important in vivo evidence for the role of POLG mutations in disease. Also, the published 3D-structure of the human pol γ assists in explaining some of the biochemical and genetic properties of the mutants. This review summarizes the current evidence that identifies and explains disease-causing POLG mutations.Keywords
This publication has 126 references indexed in Scilit:
- Mitochondrial DNA deletions in mice in men: Substantia nigra is much less affected in the mouseBiochimica et Biophysica Acta (BBA) - Bioenergetics, 2010
- Mitochondrial Fusion Is Required for mtDNA Stability in Skeletal Muscle and Tolerance of mtDNA MutationsCell, 2010
- Heteroplasmic mitochondrial DNA mutations in normal and tumour cellsNature, 2010
- Mammalian Mitochondrial DNA Replication Intermediates Are Essentially Duplex but Contain Extensive Tracts of RNA/DNA HybridJournal of Molecular Biology, 2010
- Structural Insight into Processive Human Mitochondrial DNA Synthesis and Disease-Related Polymerase MutationsCell, 2009
- Human DNA2 Is a Mitochondrial Nuclease/Helicase for Efficient Processing of DNA Replication and Repair IntermediatesMolecular Cell, 2008
- Quantification of random mutations in the mitochondrial genomeMethods, 2008
- Analysis of Rev1p and Pol ζ in mitochondrial mutagenesis suggests an alternative pathway of damage toleranceDNA Repair, 2007
- Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase γLaboratory Investigation, 2007
- Replication of vertebrate mitochondrial DNA entails transient ribonucleotide incorporation throughout the lagging strandThe EMBO Journal, 2006