OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells

Irina V Kovtun, Yuan Liu, Magnar Bjoras, Arne Klungland, Samuel H. Wilson, Cynthia T. McMurray

Research output: Contribution to journalArticle

294 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)447-452
Number of pages6
JournalNature
Volume447
Issue number7143
DOIs
StatePublished - May 24 2007
Externally publishedYes

Fingerprint

DNA Glycosylases
Poisons
Huntington Disease
DNA Repair
DNA Damage
Phenotype
Neurons
Mutation
Enzymes
7,8-dihydro-8-oxoguanine
In Vitro Techniques

ASJC Scopus subject areas

  • General

Cite this

Kovtun, I. V., Liu, Y., Bjoras, M., Klungland, A., Wilson, S. H., & McMurray, C. T. (2007). OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells. Nature, 447(7143), 447-452. https://doi.org/10.1038/nature05778

OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells. / Kovtun, Irina V; Liu, Yuan; Bjoras, Magnar; Klungland, Arne; Wilson, Samuel H.; McMurray, Cynthia T.

In: Nature, Vol. 447, No. 7143, 24.05.2007, p. 447-452.

Research output: Contribution to journalArticle

Kovtun, IV, Liu, Y, Bjoras, M, Klungland, A, Wilson, SH & McMurray, CT 2007, 'OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells', Nature, vol. 447, no. 7143, pp. 447-452. https://doi.org/10.1038/nature05778
Kovtun IV, Liu Y, Bjoras M, Klungland A, Wilson SH, McMurray CT. OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells. Nature. 2007 May 24;447(7143):447-452. https://doi.org/10.1038/nature05778
Kovtun, Irina V ; Liu, Yuan ; Bjoras, Magnar ; Klungland, Arne ; Wilson, Samuel H. ; McMurray, Cynthia T. / OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells. In: Nature. 2007 ; Vol. 447, No. 7143. pp. 447-452.
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