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Mutagenic mechanisms of cancer-associated DNA polymerase ε alleles

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Herzog, Mareike 
Alonso-Perez, Elisa 
Salguero, Israel 
Warringer, Jonas 
Adams, David 


A single amino acid residue change in the exonuclease domain of human DNA polymerase ε, P286R, is associated with the development of colorectal cancers, and has been shown to impart a mutagenic phenotype. The corresponding Pol ε allele in the yeast Saccharomyces cerevisiae ( pol2-P301R ), was found to drive greater mutagenesis than an entirely exonuclease-deficient Pol ε ( pol2-4 ), an unexpected phenotype of ultra -mutagenesis. By studying the impact on mutation frequency, type, replication-strand bias, and sequence context, we show that ultra -mutagenesis is commonly observed in yeast cells carrying a range of cancer-associated Pol ε exonuclease domain alleles. Similarities between mutations generated by these alleles and those generated in pol2-4 cells indicate a shared mechanism of mutagenesis that yields a mutation pattern similar to cancer Signature 14. Comparison of POL2 ultra -mutator with pol2-M644G , a mutant in the polymerase domain decreasing Pol ε fidelity, revealed unexpected analogies in the sequence context and strand bias of mutations. Analysis of mutational patterns unique to exonuclease domain mutant cells suggests that backtracking of the polymerase, when the mismatched primer end cannot be accommodated in the proofreading domain, results in the observed insertions and T>A mutations in specific sequence contexts.



Colorectal Neoplasms, DNA Polymerase II, DNA Replication, Humans, Mutagenesis, Mutation, Mutation Rate, Poly-ADP-Ribose Binding Proteins, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins

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Nucleic Acids Research

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Oxford University Press
Wellcome Trust (101126/Z/13/Z)
Cancer Research UK (18796)
Cancer Research UK (C6946/A24843)
Wellcome Trust (203144/Z/16/Z)
Wellcome Trust (206388/Z/17/Z)
Wellcome Trust (203144/A/16/Z)
Swedish Research Council