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Molecular and Cellular Biology, February 2003, p. 1349-1357, Vol. 23, No. 4
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.4.1349-1357.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Replication and Expansion of Trinucleotide Repeats in Yeast

Richard Pelletier,1 Maria M. Krasilnikova,2 George M. Samadashwily,2 Robert Lahue,1 and Sergei M. Mirkin2*

The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198,1 Department of Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 606072

Received 9 August 2002/ Returned for modification 30 September 2002/ Accepted 22 November 2002

The mechanisms of trinucleotide repeat expansions, underlying more than a dozen hereditary neurological disorders, are yet to be understood. Here we looked at the replication of (CGG)n · (CCG)n and (CAG)n · (CTG)n repeats and their propensity to expand in Saccharomyces cerevisiae. Using electrophoretic analysis of replication intermediates, we found that (CGG)n · (CCG)n repeats significantly attenuate replication fork progression. Replication inhibition for this sequence becomes evident at as few as ~10 repeats and reaches a maximal level at 30 to 40 repeats. This is the first direct demonstration of replication attenuation by a triplet repeat in a eukaryotic system in vivo. For (CAG)n · (CTG)n repeats, on the contrary, there is only a marginal replication inhibition even at 80 repeats. The propensity of trinucleotide repeats to expand was evaluated in a parallel genetic study. In wild-type cells, expansions of (CGG)25 · (CCG)25 and (CAG)25 · (CTG)25 repeat tracts occurred with similar low rates. A mutation in the large subunit of the replicative replication factor C complex (rfc1-1) increased the expansion rate for the (CGG)25 repeat ~50-fold but had a much smaller effect on the expansion of the (CTG)25 repeat. These data show dramatic sequence-specific expansion effects due to a mutation in the lagging strand DNA synthesis machinery. Together, the results of this study suggest that expansions are likely to result when the replication fork attempts to escape from the stall site.

* Corresponding author. Mailing address: Department of Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607. Phone: (312) 996-9610. Fax: (312) 413-0353. E-mail: mirkin{at}uic.edu.

Molecular and Cellular Biology, February 2003, p. 1349-1357, Vol. 23, No. 4
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.4.1349-1357.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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