Structure-function defects of human mitochondrial DNA polymerase in autosomal dominant progressive external ophthalmoplegia
Abstract
Progressive external ophthalmoplegia (PEO) is a mitochondrial disorder associated with mutations in the POLG gene encoding the mitochondrial DNA polymerase (pol gamma). Four autosomal dominant mutations that cause PEO encode the amino acid substitutions G923D, R943H, Y955C and A957S in the polymerase domain of pol gamma. A homology model of the pol gamma catalytic domain in complex with DNA was developed to investigate the effects of these mutations. Two mutations causing the most severe disease phenotype, Y955C and R943H, change residues that directly interact with the incoming dNTP. Polymerase mutants exhibit 0.03-30% wild-type polymerase activity and a 2- to 35-fold decrease in nucleotide selectivity in vitro. The reduced selectivity and catalytic efficiency of the autosomal dominant PEO mutants predict in vivo dysfunction, and the extent of biochemical defects correlates with the clinical severity of the disease.
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Four adPEO mutations (G923D, R943H, Y955C and A957S) were biochemically characterized.
“Four adPEO mutations (G923D, R943H, Y955C and A957S) were biochemically characterized (Graziewicz et al., 2004).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Graziewicz et al., 2004
Both R943H and Y955C alter direct interactions with incoming dNTPs resulting in severely decreased processivity and a 99% decrease in polymerase activity.
“Both R943H and Y955C alter direct interactions with incoming dNTPs resulting in severely decreased processivity and a 99% decrease in polymerase activity.”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Graziewicz et al., 2004
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- Authors
- Graziewicz, M. A., Longley, M. J., Bienstock, R. J., Zeviani, M., & Copeland, W. C.
- Affiliations
- National Institutes of Health (US)
- Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
- Corresponding author
- Copeland, William C
- Venue
- Nature Structural & Molecular Biology
- Published
- 2004-07-18
- Volume
- 11
- Issue
- 8
- Pages
- 770-776
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- OpenAlex
- W2071116588
- Cited by
- 131
- References
- 36
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 3 · 2018: 2 · 2017: 6 · 2016: 4 · 2015: 4 · 2014: 7 · 2013: 6 · 2012: 10
- FWCI
- 4.85
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- chronic progressive external ophthalmoplegia, mitochondrial DNA polymerase gamma, POLG mutations, autosomal dominant inheritance, catalytic domain, nucleotide selectivity, dNTP binding, homology model, clinical severity, mitochondrial disease
- MeSH terms
- DNA Polymerase gamma, Bacterial Proteins, DNA, DNA-Directed DNA Polymerase, Genes, Dominant, Glycine, Humans, Kinetics, Mitochondria, Models, Molecular, Mutation, Nucleotides, Protein Binding, RNA-Directed DNA Polymerase, Structure-Activity Relationship, Tyrosine, Mutagenesis, Site-Directed, Ophthalmoplegia, Chronic Progressive External, Protein Folding, Crystallography, X-Ray, Catalytic Domain, Amino Acid Motifs
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