A p.R369G POLG2 mutation associated with adPEO and multiple mtDNA deletions causes decreased affinity between polymerase γ subunits
Open accessAbstract
Human mitochondrial DNA (mtDNA) polymerase γ (pol γ) is the sole enzyme required to replicate and maintain the integrity of the mitochondrial genome. It comprises two subunits, a catalytic p140 subunit and a smaller p55 accessory subunit encoded by the POLG2 gene. We describe the molecular characterization of a potential dominant POLG2 mutation (p.R369G) in a patient with adPEO and multiple mtDNA deletions. Biochemical studies of the recombinant mutant p55 protein showed a reduced affinity to the pol γ p140 subunit, leading to impaired processivity of the holoenzyme complex but did not show sensitivity to N-ethylmalaimide (NEM) inhibition, inferring a novel disease mechanism.
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Of the handful of heterozygous mutations identified in POLG2, G451E and R369G are linked to PEO.
“Of the handful of heterozygous mutations identified in POLG2, G451E (Longley et al., 2006) and R369G (Craig et al., 2012; Young et al., 2011) are linked to PEO.”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Craig et al., 2012
G451E homodimers fail to enhance binding of PolG to DNA, while R369G has weaker binding to PolG.
“G451E homodimers also fail to enhance binding of PolG to DNA, while R369G has weaker binding to PolG.”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Craig et al., 2012
Homodimeric mutants have problems stimulating PolG processivity, with G451E being more severely defective than R396G.
“Homodimeric mutants have problems stimulating PolG processivity, with G451E being more severely defective than R396G (Craig et al., 2012; Longley et al., 2006; Young et al., 2011).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Craig et al., 2012
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- Authors
- Craig, K., Young, M. J., Blakely, E. L., Longley, M. J., Turnbull, D. M., Copeland, W. C., & Taylor, R. W.
- Affiliations
- Newcastle University (GB)
- National Institute of Environmental Health Sciences (US)
- Corresponding author
- Taylor, Robert W.
- ORCID
- Venue
- Mitochondrion
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 12
- Issue
- 2
- Pages
- 313-319
- ISSN
- 1567-7249 (ISSN-L)
- PMC
- PMC3824628
- OpenAlex
- W2092875955
- Cited by
- 24
- References
- 26
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 2 · 2020: 1 · 2019: 2 · 2018: 2 · 2017: 2 · 2016: 4 · 2015: 2 · 2014: 3 · 2013: 2 · 2012: 2
- FWCI
- 0.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Mitochondrion (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Wellcome Trust Programme (074454/Z/04/Z)
- UK NHS Specialist Commissioners
- NIH, National Institute of Environmental Health Sciences (ES 065078)
- 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 › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- POLG2, chronic progressive external ophthalmoplegia, mitochondrial DNA polymerase gamma, protein-protein interaction, polymerase processivity, N-ethylmaleimide sensitivity, dominant mutations, disease mechanisms
- MeSH terms
- DNA-Directed DNA Polymerase, DNA, Mitochondrial, Humans, Male, Middle Aged, Protein Binding, Ophthalmoplegia, Chronic Progressive External, Sequence Deletion, Protein Subunits, Protein Multimerization
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