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Molecular and Cellular Biology, March 2004, p. 2286-2295, Vol. 24, No. 6
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.6.2286-2295.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Replication Stalling at Friedreich's Ataxia (GAA)n Repeats In Vivo

Maria M. Krasilnikova and Sergei M. Mirkin*

Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 60607

Received 21 November 2003/ Returned for modification 16 December 2003/ Accepted 22 December 2003

Friedreich's ataxia (GAA)n repeats of various lengths were cloned into a Saccharymyces cerevisiae plasmid, and their effects on DNA replication were analyzed using two-dimensional electrophoresis of replication intermediates. We found that premutation- and disease-size repeats stalled the replication fork progression in vivo, while normal-size repeats did not affect replication. Remarkably, the observed threshold repeat length for replication stalling in yeast (~40 repeats) closely matched the threshold length for repeat expansion in humans. Further, replication stalling was strikingly orientation dependent, being pronounced only when the repeat's homopurine strand served as the lagging strand template. Finally, it appeared that length polymorphism of the (GAA)n · (TTC)n repeat in both expansions and contractions drastically increases in the repeat's orientation that is responsible for the replication stalling. These data represent the first direct proof of the effects of (GAA)n repeats on DNA replication in vivo. We believe that repeat-caused replication attenuation in vivo is due to triplex formation. The apparent link between the replication stalling and length polymorphism of the repeat points to a new model for the repeat expansion.

* Corresponding author. Mailing address: Department of Biochemistry and 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, March 2004, p. 2286-2295, Vol. 24, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.6.2286-2295.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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