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OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells

Author

Listed:
  • 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,
    Department of Biochemistry and Molecular Biology,
    Neuroscience Program Mayo Clinic and Foundation, 200 First Street SW, Rochester, Minnesota 55905, USA)

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.

Suggested Citation

  • Irina V. Kovtun & Yuan Liu & Magnar Bjoras & Arne Klungland & Samuel H. Wilson & Cynthia T. McMurray, 2007. "OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells," Nature, Nature, vol. 447(7143), pages 447-452, May.
    • Handle: RePEc:nat:nature:v:447:y:2007:i:7143:d:10.1038_nature05778
    DOI: 10.1038/nature05778
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