OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells

• Published in: Nature 2007-05, Vol.447 (7143), p.447-452
• Main Authors: Kovtun, Irina V., Liu, Yuan, Bjoras, Magnar, Klungland, Arne, Wilson, Samuel H., McMurray, Cynthia T.
• Format: Article
• Language: English
• Subjects: Aging; Aging - genetics; Animals; Biological and medical sciences; Biomedical research; Cell Line; Cellular biology; Deoxyribonucleic acid; DNA; DNA Breaks, Single-Stranded; DNA Damage; DNA Glycosylases - deficiency; DNA Glycosylases - genetics; DNA Glycosylases - metabolism; DNA Repair - genetics; Female; Fundamental and applied biological sciences. Psychology; Genotype & phenotype; Guanosine - analogs & derivatives; Guanosine - metabolism; Humanities and Social Sciences; Humans; Huntington Disease - genetics; Lesions; Male; Mice; Models, Genetic; Molecular and cellular biology; Molecular genetics; multidisciplinary; Mutagenesis. Repair; Mutation; Neurology; Neurons - metabolism; Oxidation; Oxidation-Reduction; Science; Science (multidisciplinary); Trinucleotide Repeat Expansion - genetics
• ISSN: 0028-0836; 1476-4687; 1476-4679
• DOI: 10.1038/nature05778

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. Trigger for Huntington's Oxidative damage has been linked to ageing and neurodegenerative disease for decades, but the physiological link between oxidation and the genetics of ageing remains elusive. Now it may have been found. Huntington's and several other neurodegenerative diseases involve the expansion of CAG triplet repeats. In a mouse model of human Huntington's disease, this expansion occurs in mid-life and continues throughout life. The expansion occurs in terminally differentiated cells and is associated with oxidative damage. Deficiency in the glycolase OGG1 attenuates age-dependent repeat expansion, and as OGG1 is a DNA repair enzyme, it seems that aberrant repair of oxidative damage triggers the disease. This work suggests targets for drugs to stop or slow the onset of the disease. Several neurodegenerative diseases are caused by expansion of CAG triplet repeats, and, using a mouse model of human Huntington's disease, this study shows that this expansion occurs in mid-life and continues throughout life; furthermore, the expansion occurs in terminally differentiated cells. This is associated with oxidative damage, and deficiency in OGG1, a DNA repair enzyme, attenuates age-dependent repeat expansion — thus it seems that aberrant repair of oxidative damage is the basis for this disease.