Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair

The genomes of all eukaryotes contain tracts of DNA in which a single base or a small number of bases is repeated. Expansions of such tracts have been associated with several human disorders including the fragile X syndrome. In addition, simple repeats are unstable in certain forms of colorectal can...

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Bibliographic Details
Published in:Nature (London) 1993-09, Vol.365 (6443), p.274-276
Main Authors: Strand, Micheline, Prolla, Tomas A, Liskay, R. Michael, Petes, Thomas D
Format: Article
Language:English
Subjects:
Biochemistry
Biological and medical sciences
Colorectal carcinoma
Deoxyribonucleic acid
DNA
DNA Repair - genetics
DNA Replication
DNA, Fungal - biosynthesis
DNA, Fungal - genetics
DNA, Fungal - metabolism
DNA-Directed DNA Polymerase - metabolism
Fundamental and applied biological sciences. Psychology
Genes, Fungal
Genes. Genome
Medical research
Molecular and cellular biology
Molecular genetics
Mutation
Nucleic Acid Heteroduplexes - genetics
Nucleic Acid Heteroduplexes - metabolism
Plasmids
Polydeoxyribonucleotides - metabolism
Recombination, Genetic
Repetitive Sequences, Nucleic Acid
Saccharomyces cerevisiae
Yeast
Yeasts
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Summary:The genomes of all eukaryotes contain tracts of DNA in which a single base or a small number of bases is repeated. Expansions of such tracts have been associated with several human disorders including the fragile X syndrome. In addition, simple repeats are unstable in certain forms of colorectal cancer, suggesting a defect in DNA replication or repair. We show here that mutations in any three yeast genes involved in DNA mismatch repair (PMS1, MLH1 and MSH2) lead to 100- to 700-fold increases in tract instability, whereas mutations that eliminate the proof-reading function of DNA polymerases have little effect. The meiotic stability of the tracts is similar to the mitotic stability. These results suggest that tract instability is associated with DNA polymerases slipping during replication, and that some types of colorectal cancer may reflect mutations in genes involved in DNA mismatch repair.
ISSN:0028-0836
1476-4687
DOI:10.1038/365274a0