OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells
Open accessAbstract
Although oxidative damage has long been associated with ageing and neurological disease, mechanistic connections of oxidation to these phenotypes have remained elusive. Here we show that the age-dependent somatic mutation associated with Huntington's disease occurs in the process of removing oxidized base lesions, and is remarkably dependent on a single base excision repair enzyme, 7,8-dihydro-8-oxoguanine-DNA glycosylase (OGG1). Both in vivo and in vitro results support a 'toxic oxidation' model in which OGG1 initiates an escalating oxidation-excision cycle that leads to progressive age-dependent expansion. Age-dependent CAG expansion provides a direct molecular link between oxidative damage and toxicity in post-mitotic neurons through a DNA damage response, and error-prone repair of single-strand breaks.
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CAG expansion in HD is dependent upon DNA repair proteins such as OGG1, MLH1, and MSH2.
“Notably, CAG expansion has been found to be dependent upon DNA repair proteins such as OGG1, MLH1, and MSH2, whose detection of oxidized or mismatched bases in these repetitive elements could potentially elicit erroneous repair, leading to CAG expansion (Kovtun et al, 2007; Bettencourt et al, 2016; Pinto et al, 2013; Manley et al, 1999; Lee et al, 2017, 1).”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Kovtun et al, 2007
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- Authors
- Kovtun, I. V., Liu, Y., Bjoras, M., Klungland, A., Wilson, S. H., & McMurray, C. T.
- Affiliations
- Mayo Clinic (US)
- National Institutes of Health (US)
- Oslo University Hospital (NO)
- Corresponding author
- McMurray, Cynthia T.
- Venue
- Nature
- Published
- 2007-04-22
- Volume
- 447
- Issue
- 7143
- Pages
- 447-452
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2681094
- OpenAlex
- W2006764478
- Cited by
- 433
- References
- 46
- Citations by year
- 2026: 1 · 2025: 20 · 2024: 20 · 2023: 6 · 2022: 15 · 2021: 24 · 2020: 22 · 2019: 16 · 2018: 21 · 2017: 12 · 2016: 32 · 2015: 22 · 2014: 27 · 2013: 32 · 2012: 36
- FWCI
- 11.81
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Mayo Foundation for Medical Education and Research
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM066359)
- National Institute of Neurological Disorders and Stroke (R01NS040738)
- National Institute of Environmental Health Sciences (Z01ES050158)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- OGG1, CAG repeat expansion, Huntington's disease, oxidative DNA damage, base excision repair, somatic mutations, neurodegenerative diseases, DNA glycosylase, single-strand break repair, DNA damage response, postmitotic neurons
- MeSH terms
- Aging, Animals, Cell Line, DNA Damage, DNA Repair, Female, Guanosine, Humans, Huntington Disease, Male, Models, Genetic, Neurons, Oxidation-Reduction, Trinucleotide Repeat Expansion, DNA Glycosylases, Mice, DNA Breaks, Single-Stranded
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