Destabilization of CAG trinucleotide repeat tracts by mismatch repair mutations in yeast

Jill Kuglin Schweitzer, Dennis M. Livingston

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

Abstract

To examine the genetic factors that affect the stability of disease-associated trinucleotide repeats, we have assessed the stability of CAG repeats in yeast strains with mutations in the mismatch repair system. We have found that both pmsl and msh2 mutations destabilize repeat tracts. Destabilization is evidenced both by the increased frequency of repeat length changes and in the pattern of changes that are observed. In wild-type cells repeats are relatively stable when CAG serves as the lagging strand template but relatively unstable when CTG serves as the lagging strand template, Large contractions in repeat length are the most common change. In pmsl and msh2 mutants the relatively stable tracts incur more tract length changes. In addition, many small deletions and some small additions, most often of one repeat unit, are frequent in repeats of the stable orientation. These small changes also are seen as a new class of events that occur in repeats in the unstable orientation. The results show that in yeast the mismatch repair system prevents small changes from occurring but cannot prevent larger changes from occurring.

Original languageEnglish (US)
Pages (from-to)349-355
Number of pages7
JournalHuman molecular genetics
Volume6
Issue number3
DOIs
StatePublished - Mar 1997

Bibliographical note

Funding Information:
This work was supported by grant P01NS33718 from the National Institutes of Health. We thank Debra Maurer and Brennon O’Callaghan for technical help and Richard Kolodner (Dana-Farber Cancer Institute) for supplying disruptions of PMS1 and MSH2. We thank Harry Orr for his encouragement and for his comments on the manuscript.

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