title: Disease-associated CAG·CTG triplet repeats expand rapidly in non-dividing mouse cells, but cell cycle arrest is insufficient to drive expansion.
abstract: Genetically unstable expanded CAG·CTG trinucleotide repeats are causal in a number of human disorders, including Huntington disease and myotonic dystrophy type 1. It is still widely assumed that DNA polymerase slippage during replication plays an important role in the accumulation of expansions. Nevertheless, somatic mosaicism correlates poorly with the proliferative capacity of the tissue and rates of cell turnover, suggesting that expansions can occur in the absence of replication. We monitored CAG·CTG repeat instability in transgenic mouse cells arrested by chemical or genetic manipulation of the cell cycle and generated unequivocal evidence for the continuous accumulation of repeat expansions in non-dividing cells. Importantly, the rates of expansion in non-dividing cells were at least as high as those of proliferating cells. These data are consistent with a major role for cell division-independent expansion in generating somatic mosaicism in vivo. Although expansions can accrue in non-dividing cells, we also show that cell cycle arrest is not sufficient to drive instability, implicating other factors as the key regulators of tissue-specific instability. Our data reveal that de novo expansion events are not limited to S-phase and further support a cell division-independent mutational pathway.
authors.affiliation: Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK Inserm UMR 1163, Laboratory of CTG Repeat Instability and Myotonic Dystrophy Type 1, 75015 Paris, France Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France mario.pereira@inserm.fr.
authors.forename: Mário
authors.initials: M
authors.lastname: Gomes-Pereira
authors.affiliation: Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: James D
authors.initials: JD
authors.lastname: Hilley
authors.affiliation: Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK Instituto de Investigaciones en Salud y Escuela de Medicina, Universidad de Costa Rica, San José, Costa Rica.
authors.forename: Fernando
authors.initials: F
authors.lastname: Morales
authors.affiliation: Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Berit
authors.initials: B
authors.lastname: Adam
authors.affiliation: Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Helen E
authors.initials: HE
authors.lastname: James
authors.affiliation: Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK mario.pereira@inserm.fr.
authors.forename: Darren G
authors.initials: DG
authors.lastname: Monckton
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D051379:Mice; D008822:Mice, Transgenic; D009422:Nervous System Diseases / Q000235:genetics; D019680:Trinucleotide Repeat Expansion