title: OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells.
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.
authors: Department of Pharmacology and Experimental Therapeutics, Mayo Clinic and Foundation, 200 First Street SW, Rochester, Minnesota 55905, USA.
authors: Irina V
authors: IV
authors: Kovtun
authors: Yuan
authors: Y
authors: Liu
authors: Magnar
authors: M
authors: Bjoras
authors: Arne
authors: A
authors: Klungland
authors: Samuel H
authors: SH
authors: Wilson
authors: Cynthia T
authors: CT
authors: McMurray
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D053904:DNA Breaks, Single-Stranded; D004249:DNA Damage; D045647:DNA Glycosylases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair / Q000235:genetics; D005260:Female; D006151:Guanosine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000235:genetics; D008297:Male; D051379:Mice; D008957:Models, Genetic; D009474:Neurons / Q000378:metabolism*; D010084:Oxidation-Reduction; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D006151:Guanosine; C046215:8-hydroxyguanosine; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse