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.

• PMID: 16979389
• DOI full text
• PubMed
• PubTator

Reference Type

Journal Article | Research Support, N.I.H., Extramural

Authors

Collins NS, Bhattacharyya S, Lahue RS

Primary Lit For

Additional Lit For

Review For