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DNA replication error-induced extinction of diploid yeast.

Alan J Herr1, Scott R Kennedy, Gary M Knowels

  • 1Department of Pathology, University of Washington, Seattle, Washington 98195.

Genetics
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Summary

Diploid cells tolerate 10 times higher mutation rates than haploid cells before extinction. High mutation rates, even below the lethal threshold, cause significant fitness loss, suggesting therapeutic vulnerabilities in mutator-driven cancers.

Keywords:
DNA replication and repaircancerlethal mutagenesismutational robustnesspolymerase fidelity

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Area of Science:

  • Genetics
  • Molecular Biology
  • Cell Biology

Background:

  • Genetic defects in DNA repair mechanisms like DNA polymerase accuracy, proofreading, and mismatch repair (MMR) can lead to mutator phenotypes.
  • These mutator phenotypes accelerate adaptation in microbes and tumor cells, with certain combinations of mutations driving haploid cell extinction.
  • The maximum mutation rate tolerated by diploid cells remains largely undefined.

Purpose of the Study:

  • To determine the threshold for replication error-induced extinction (EEX) in diploid Saccharomyces cerevisiae.
  • To investigate the synergistic effects of different DNA repair defects on mutation rates and cell viability.
  • To explore the role of the S-phase checkpoint kinase Dun1 in suppressing mutator phenotypes and lethality.

Main Methods:

  • Creation of double-mutant pol3 alleles with defects in DNA polymerase-δ proofreading and accuracy.
  • Analysis of heterozygous and homozygous states of these pol3 alleles in diploid yeast.
  • Introduction of antimutator eex mutations and MMR defects.
  • Assessment of cell cycle arrest, mutation rates, and growth impairment.
  • Inactivation of the Dun1 S-phase checkpoint kinase.

Main Results:

  • Heterozygous diploids with specific pol3 double-mutant alleles exhibited strong mutator phenotypes.
  • Homozygous pol3-01,L612M and pol3-01,L612G alleles were lethal, causing cell cycle arrest after several divisions.
  • Antimutator eex mutations suppressed the lethality of these pol3 alleles.
  • MMR defects synergized with certain pol3 alleles, increasing mutation rates and reducing growth.
  • Dun1 kinase inactivation suppressed both mutator phenotypes and the lethal pol3-01,L612M phenotype.

Conclusions:

  • The lethal error threshold for diploid cells is approximately 10 times higher than for haploid cells, likely linked to homozygous inactivation of essential genes.
  • Significant fitness decline occurs at mutation rates substantially lower than the lethal threshold.
  • These findings suggest that cancers driven by mutator phenotypes might be treatable with drugs that increase replication errors.