Disease-associated CAG•CTG triplet repeats expand rapidly in non-dividing mouse cells, but cell cycle arrest is insufficient to drive expansion

Gomes-Pereira, M., Hilley, J. D.,, Morales Montero, F., Adam, B., James, H. E. and Monckton, D. G. (2014) Disease-associated CAG•CTG triplet repeats expand rapidly in non-dividing mouse cells, but cell cycle arrest is insufficient to drive expansion. Nucleic Acids Research, 42(11), pp. 7047-7056. (doi:10.1093/nar/gku285)

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Publisher's URL: http://dx.doi.org/10.1093/nar/gku285

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Monckton, Professor Darren and Morales Montero, Mr Fernando and Hilley, Dr James and Adam, Mrs Berit
Authors: Gomes-Pereira, M., Hilley, J. D.,, Morales Montero, F., Adam, B., James, H. E., and Monckton, D. G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Nucleic Acids Research
Publisher:Oxford University Press
ISSN:0305-1048
ISSN (Online):1362-4962
Copyright Holders:Copyright © 2014 The Authors
First Published:First published in Nucleic Acids Research 42(11):7047-7056
Publisher Policy:Reproduced under a Creative Commons License
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
313831Trans-acting chemical modifiers of DNA repeat stability in in vitro and in vivo - towards novel therapies in the triplet repeat expansion...Darren MoncktonWellcome Trust (WELLCOME)066213/Z/01/ZRI MOLECULAR CELL & SYSTEMS BIOLOGY