Mutator suppression and escape from replication error-induced extinction in yeast

Area of Science:

• Genetics
• Molecular Biology
• Cell Biology

Background:

• Cellular DNA replication fidelity is maintained by conserved pathways, including polymerase proofreading and mismatch repair.
• Loss of these repair mechanisms increases mutation rates, which can aid cellular adaptation but may lead to inviability if mutation rates become too high.

Purpose of the Study:

• To determine the maximal tolerable mutation rate in haploid yeast.
• To identify genetic suppressors of mutator phenotypes and understand mechanisms of adaptation to high mutation rates.

Main Methods:

• Combining alleles affecting DNA polymerase delta (Pol δ) proofreading and mismatch repair in yeast.
• Quantifying mutation rates and identifying genetic variants that escape error-induced extinction.

Main Results:

• Yeast populations can tolerate mutation rates up to 1,000-fold higher than wild-type levels.
• Cellular collapse occurs when mutation rates exceed 10⁻³ inactivating mutations per gene per cell division.
• Genetic adaptation, through Pol δ mutations or extragenic changes, rapidly suppresses mutator phenotypes.

Conclusions:

• Mutator phenotypes in eukaryotes are transient and subject to rapid genetic suppression.
• Adaptation mechanisms involve both direct suppression of polymerase errors and broader genetic changes.
• Understanding mutator suppression is crucial for comprehending their role in cancer development.