Cited by 131Mitochondrial Function and PathologyDNA Repair MechanismsGenomics and Rare Diseases

Structure-function defects of human mitochondrial DNA polymerase in autosomal dominant progressive external ophthalmoplegia

Graziewicz, Maria A, Longley, Matthew J, Bienstock, Rachelle J, Zeviani, Massimo, Copeland, William C·2004·Nature Structural & Molecular Biology

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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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
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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