OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells

Article

关键词: BASE-EXCISION-REPAIR;    CAG/CTG TRIPLET REPEATS;    HUNTINGTON-DISEASE;    SUBSTRATE-SPECIFICITY;    HUMAN DNA;    INSTABILITY;    MICE;    MECHANISM;    GLYCOSYLASE;    TOXICITY;   

DOI  :  10.1038/nature05778

来源: SCIE

【 摘 要 】

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.

【 授权许可】

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