title: Oxidative stress causes DNA triplet expansion in Huntington's disease mouse embryonic stem cells.
abstract: Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded trinucleotide CAG repeat in the Huntingtin (Htt) gene. The molecular basis for the development and progression of HD is currently poorly understood. However, different DNA repair pathways have been implicated in both somatic expansion and disease progression. Embryonic stem cells provide a remarkable in vitro system to study HD and could have implications for understanding disease development and for therapeutic treatment. Here, we derive pluripotent stem cells from the mouse R6/1 HD model and demonstrate that repeated exposure to genotoxic agents inducing oxidative DNA damage gave a significant and dose dependent increase in somatic triplet expansion. Further investigation into specific steps of DNA repair revealed impaired double stranded break repair in exposed R6/1 cells, accompanied by the induction of apoptosis. We also found that differentiation status, and consequently DNA repair efficiency influenced somatic expansion. Our data underscore the importance of DNA damage and repair for the stability of the HD triplet in pluripotent stem cells.
authors.affiliation: Clinic for Diagnostics and Intervention and Institute of Medical Microbiology, Oslo University Hospital, Rikshospitalet and University of Oslo, NO-0027 Oslo, Norway.
authors.forename: Ida
authors.initials: I
authors.lastname: Jonson
authors.forename: Rune
authors.initials: R
authors.lastname: Ougland
authors.forename: Arne
authors.initials: A
authors.lastname: Klungland
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Larsen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation; D004247:DNA / Q000378:metabolism*; D004260:DNA Repair; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D005838:Genotype; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology; D006861:Hydrogen Peroxide / Q000633:toxicity; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D019680:Trinucleotide Repeat Expansion / Q000187:drug effects
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D004247:DNA; D006861:Hydrogen Peroxide