OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells

Irina V. Kovtun, Yuan Liu, Magnar Bjoras, Arne Klungland, Samuel H. Wilson and Cynthia T. McMurray ()
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Irina V. Kovtun: Department of Pharmacology and Experimental Therapeutics,
Yuan Liu: Laboratory of Structural Biology, National Institute of Environmental Health Sciences/National Institutes of Health, 111 TW Alexander Drive, Research Triangle Park, North Carolina 27709, USA
Magnar Bjoras: Centre for Molecular Biology and Neuroscience and Institute of Medical Microbiology, Rikshospitalet-Radiumhospitalet HF, University of Oslo, N-0027 Oslo, Norway
Arne Klungland: Centre for Molecular Biology and Neuroscience and Institute of Medical Microbiology, Rikshospitalet-Radiumhospitalet HF, University of Oslo, N-0027 Oslo, Norway
Samuel H. Wilson: Laboratory of Structural Biology, National Institute of Environmental Health Sciences/National Institutes of Health, 111 TW Alexander Drive, Research Triangle Park, North Carolina 27709, USA
Cynthia T. McMurray: Department of Pharmacology and Experimental Therapeutics,

Nature, 2007, vol. 447, issue 7143, 447-452

Abstract: Abstract 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.

Date: 2007
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DOI: 10.1038/nature05778

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