Book of Abstracts: Albany 2005
CAG Expansion is Caused in the Process Of 8-Oxo-G Removal
Mammalian cells have evolved sophisticated DNA repair systems to correct mispaired or damaged bases and extra helical loops. However, we find that two DNA repair systems, the mismatch recognition system (MMR) and the base excision repair, are turned into a causative factor rather than a safeguard of genomic integrity. We have followed CAG expansion in germ cells and in somatic tissues of transgenic mice harboring a fragment of the human Huntington?s disease (HD) gene. CAG expansion of the hHD allele is abrogated in both somatic cells and in germ cells of transgenic mice that lack Msh2. A complex involving Msh2 is thought to cause expansions by binding to, but failing to correct at the site of DNA breaks. Base excision repair may cause the break that needs to be repaired. Surprisingly, expansion in somatic cells only occurs at midlife of the mouse. These data indicate that some process associated with aging causes expansion and DNA breaks only in midlife. Consistent with this hypothesis, age-dependent expansion can be caused in the process of repairing single strand breaks by base excision repair. Oxidized bases generated by exposure to hydrogen peroxide can cause expansion of CAG repeats in the brains of transgenic mice expressing the mutant form of the huntingtin gene product. In mice, we find an increase in 8-OXO-Guanine increases with age of the animals and in the relevant tissues. We find that loss of OGG1 in mice stops expansion. The timing of excision repair may correlate with the late onset nature of the disease.
1Departments of Molecular Pharmacology and Experimental Therapeutics