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Molecular and Cellular Biology, November 2003, p. 7849-7860, Vol. 23, No. 21
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.21.7849-7860.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Mutations in Yeast Replication Proteins That Increase CAG/CTG Expansions Also Increase Repeat Fragility

Julie L. Callahan,1,{dagger} Kenneth J. Andrews,1,{ddagger} Virginia A. Zakian,3 and Catherine H. Freudenreich1,2*

Department of Biology,1 Program in Genetics, Tufts University, Medford, Massachusetts 02155,2 Department of Molecular Biology, Princeton University, Princeton, New Jersey 085443

Received 20 March 2003/ Returned for modification 12 May 2003/ Accepted 14 July 2003

Expansion of trinucleotide repeats (TNRs) is the causative mutation in several human genetic diseases. Expanded TNR tracts are both unstable (changing in length) and fragile (displaying an increased propensity to break). We have investigated the relationship between fidelity of lagging-strand replication and both stability and fragility of TNRs. We devised a new yeast artificial chromomosme (YAC)-based assay for chromosome breakage to analyze fragility of CAG/CTG tracts in mutants deficient for proteins involved in lagging-strand replication: Fen1/Rad27, an endo/exonuclease involved in Okazaki fragment maturation, the nuclease/helicase Dna2, RNase HI, DNA ligase, polymerase {delta}, and primase. We found that deletion of RAD27 caused a large increase in breakage of short and long CAG/CTG tracts, and defects in DNA ligase and primase increased breakage of long tracts. We also found a correlation between mutations that increase CAG/CTG tract breakage and those that increase repeat expansion. These results suggest that processes that generate strand breaks, such as faulty Okazaki fragment processing or DNA repair, are an important source of TNR expansions.

* Corresponding author. Mailing address: Department of Biology, Dana 120, Tufts University, Medford, MA 02155. Phone: (617) 627-4037. Fax: (617) 627-3805. E-mail: catherine.freudenreich{at}tufts.edu.

{dagger} Present address: Department of Entomology, University of Massachusetts, Amherst, MA 01003.

{ddagger} Present address: Molecular Biophysics & Biochemistry Department, Yale University, New Haven, CT 06520-8114.

Molecular and Cellular Biology, November 2003, p. 7849-7860, Vol. 23, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.21.7849-7860.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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