OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells.
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.
Kovtun
Irina V
IV
Department of Pharmacology and Experimental Therapeutics, Mayo Clinic and Foundation, 200 First Street SW, Rochester, Minnesota 55905, USA.
Liu
Yuan
Y
Bjoras
Magnar
M
Klungland
Arne
A
Wilson
Samuel H
SH
McMurray
Cynthia T
CT
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*
D006151:Guanosine; C046215:8-hydroxyguanosine; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse