Exo1‐independent MMR at euchromatin is error‐prone and involves Pol ζ and Rev1

Abstract

Genomes are under a constant attack by exogenous and endogenous agents that cause various forms of DNA damage. If the DNA damage is left unrepaired, it leads to a mutation. The mutation might alter the cell’s phenotype and trigger a disease. DNA repair processes and the high‐fidelity DNA replication play an important role in maintaining genome integrity. DNA mismatch repair (MMR) is a key DNA repair process that corrects DNA replication errors that have escaped proofreading. MMR can occur in an error‐free and error‐prone manner. Both error‐free and error‐prone MMR mechanisms have a strong impact on human health. Previous research has established that the exonuclease Exo1 is a non‐essential MMR factor that participates in MMR by removing the DNA mismatch in a 5′→3′ hydrolytic reaction. We have found that the Exo1‐independent MMR at euchromatin is error prone and occurs in a DNA polymerase (Pol) ζ‐ and DNA polymerase Rev1‐dependent manner. Surprisingly, the Pol ζ‐ and Rev1‐dependent error‐prone MMR does not involve PCNA K164 residue and ubiquitin ligase Siz1, factors that cooperate with Pol ζ in other DNA transactions. Our results have suggested that a novel error prone MMR mechanism is activated in response to the loss of a non‐essential MMR factor.Support or Funding InformationNational Institute of General Medical Sciences of the National Institutes of Health under Award Number R01GM095758 Spontaneous CAN1 mutation rates in euchromatic CAN1 gene Genotype CAN1 mutation rate Absolute rate (×10−8) 95% CI (×10−8) Relative rate Wild‐type 19 16–24 1 exo1Δ 120n,q 100–190 6 pol30‐K164R 24 18–31 1 msh2Δ 600p 450–800 32 pol30‐K164R msh2Δ 550p 400–650 29 pol30‐K164R exo1Δ 120q 100–190 6 siz1Δ 29 17–42 1.5 exo1Δ siz1Δ 120n 73–160 6 The mutant strains are isogenic to E134 (wild type). CI represents 95% confidence interval. The mutation rates marked n,p,q do not statistically differ from each other. p=0.5, 0.06, 0.1 respectively.