Rev1 enhances CAG.CTG repeat stability in Saccharomyces cerevisiae.
Trinucleotide repeats (TNRs) frequently expand in certain human genetic diseases, often with devastating pathological consequences. TNR expansions require the addition of new DNA; accordingly, molecular models suggest aberrant DNA replication or error-prone repair synthesis as the sources of most instability. Some proteins are currently known that either promote or inhibit TNR mutability. To identify additional proteins that help protect cells against TNR instability, yeast mutants were isolated with higher than normal rates of CAG.CTG tract expansions. Surprisingly, a rev1 mutant was isolated. In contrast to its canonical function in supporting mutagenesis, we found that Rev1 reduces rates of CAG.CTG repeat expansions and contractions, as judged by the behavior of the rev1 mutant. The rev1 mutator phenotype was specific for TNRs with hairpin forming capacity. Mutations in REV3 or REV7, encoding the subunits of DNA polymerase zeta (pol zeta), did not affect expansion rates in REV1 or rev1 strains. A rev1 point mutant lacking dCMP transferase activity was normal for TNR instability, whereas the rev1-1 allele that interferes with BRCT domain function was as defective as a rev1 null mutant. In summary, these results indicate that yeast Rev1 reduces mutability of CAG.CTG tracts in a manner dependent on BRCT domain function but independent of dCMP transferase activity and of pol zeta.
Collins
Natasha S
NS
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Box 986805, Omaha, NE 68198-6805, United States.
Bhattacharyya
Saumitri
S
Lahue
Robert S
RS
D004260:DNA Repair; D004261:DNA Replication; D004271:DNA, Fungal / Q000235:genetics* / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009713:Nucleotidyltransferases / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion; D000099270:Y-Family DNA Polymerases
D004271:DNA, Fungal; D004259:DNA-Directed DNA Polymerase; D009713:Nucleotidyltransferases; D029701:Saccharomyces cerevisiae Proteins; C092219:REV7 protein, S cerevisiae; C425929:DNA polymerase zeta; C100951:REV1 protein, S cerevisiae; D000099270:Y-Family DNA Polymerases; C092602:REV3 protein, S cerevisiae