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Published online 20 May 2004

Nucleic Acids Research, 2004, Vol. 32, No. 9 2865-2872
© 2004 Oxford University Press

Chemically induced increases and decreases in the rate of expansion of a CAG·CTG triplet repeat

Mário Gomes-Pereira and Darren G. Monckton*

Institute of Biomedical and Life Sciences, University of Glasgow, Anderson College Building, 56 Dumbarton Road, Glasgow G11 6NU, UK

*To whom correspondence should be addressed. Tel: +44 141 330 6213; Fax: +44 141 330 6871; Email: d.monckton{at}bio.gla.ac.uk

Received March 22, 2004; Revised and Accepted April 26, 2004

Somatic mosaicism of repeat length is prominent in repeat expansion disorders such as Huntington disease and myotonic dystrophy. Somatic mosaicism is age-dependent, tissue-specific and expansion-biased, and likely contributes toward the tissue-specificity and progressive nature of the symptoms. We propose that therapies targeted at somatic repeat expansion may have general utility in these disorders. Specifically, suppression of somatic expansion would be expected to be therapeutic, whilst reversion of the expanded mutant repeat to within the normal range would be predicted to be curative. However, the effects of genotoxic agents on the mutational properties of specific nuclear genes are notoriously difficult to define. Nonetheless, we have determined that chronic exposure over a three month period to a number of genotoxic agents can alter the rate of triplet repeat expansion in whole populations of mammalian cells. Interestingly, high doses of caffeine increased the rate of expansion by ~60%. More importantly, cytosine arabinoside, ethidium bromide, 5-azacytidine and aspirin all significantly reduced the rate of expansion by from 35 to 75%. These data establish that drug induced suppression of somatic expansion is possible. These data also suggest that highly unstable expanded simple sequence repeats may act as sensitive reporters of genotoxic assault in the soma.


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