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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.

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Figure 1: Oxidative lesions accumulate in tissues of ageing mice.
Figure 2: Direct exposure to oxidizing agents causes expansion at the human HD locus in vitro.
Figure 3: Age-dependent expansion is suppressed in mice lacking OGG1 glycosylase.
Figure 4: OGG1 excision of 8-oxo-G within CAG repeat DNA can initiate strand displacement and expansion in vitro during BER.

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Acknowledgements

This work was supported by the Mayo Foundation, the National Institutes of Health (C.T.M.), and, in part, by the Intramural Research Program of the National Institute of Environmental Health Sciences. The authors wish to dedicate this work to Erling Seeberg. We thank J. Hoeijmakers for NTH-/- and L. Samson for AAG-/- mice, and N. Kinzel for help in cortex dissection.

Author Contributions C.T.M. oversaw the entire project. I.V.K. and C.T.M. conceived the experiments, wrote the manuscript, and prepared all Figures. I.V.K. carried out in vitro and in vivo experiments in cell lines and in mice (animal breeding, oxidation, comet assay, FACS, analysis of repeat size, dissected animal tissue) and prepared tissue extracts for all testing of repair activity in vitro, and performed analysis of the results. Y.L. with S.H.W. supervision performed base excision repair reconstitution experiments, M.B. and A.K. carried out DNA repair assays. All co-authors contributed to the manuscript with their comments.

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Kovtun, I., Liu, Y., Bjoras, M. et al. OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells. Nature 447, 447–452 (2007). https://doi.org/10.1038/nature05778

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