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Spontaneous frameshift mutations in Saccharomyces cerevisiae: accumulation during DNA replication and removal by

C N Greene1, S Jinks-Robertson

  • 1Graduate Program in Genetics and Molecular Biology, Emory University, Atlanta, Georgia 30322, USA.

Genetics
|September 19, 2001
PubMed

Insights

DNA repair mechanisms, including exonucleolytic proofreading and mismatch repair, are crucial for preventing frameshift mutation accumulation during DNA replication. Yeast studies reveal distinct roles for these pathways in maintaining replication fidelity.

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • Frameshift mutations arise from errors during DNA replication, specifically the generation and resolution of frameshift intermediates.
  • Replication fidelity is maintained by DNA polymerase proofreading and postreplicative mismatch repair (MMR) systems.
  • Understanding the interplay between these repair pathways is essential for comprehending mutation accumulation.

Purpose of the Study:

  • To investigate the relative contributions of DNA polymerase proofreading and MMR to replication fidelity in Saccharomyces cerevisiae.
  • To analyze the impact of specific mutations in DNA polymerases delta and epsilon, and the MSH2 gene (involved in MMR), on frameshift mutation rates and spectra.
  • To determine how defects in these repair systems influence the correlation between homopolymer run length and frameshift accumulation.

Main Methods:

  • Determined frameshift allele reversion rates and spectra in wild-type and mutant yeast strains.
  • Utilized strains with defects in the exonuclease activities of DNA polymerases delta (pol3-01) and epsilon (pol2-4).
  • Assessed the role of mismatch repair by analyzing strains with MSH2 deletions, including combinations of all repair defects.

Main Results:

  • A direct correlation between homopolymer run length and frameshift accumulation was observed only in the triple mutant lacking all repair capacity.
  • Strains with defects in one or two repair activities showed distinct biases in the removal of frameshift intermediates.
  • Exonuleolytic proofreading and MMR exhibit specific roles in correcting different types of frameshift errors.

Conclusions:

  • Both exonucleolytic proofreading and mismatch repair are critical for preventing frameshift mutation accumulation.
  • The relative importance of each repair pathway depends on the specific type of frameshift intermediate.
  • The mismatch repair machinery may actively contribute to the generation of certain frameshift mutations in yeast.

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