Homo sapiens Raw sequence reads. Homo sapiens

We set out to test the contributions of mismatch repair (MMR) to exonuclease-deficient Pol ε mutagenesis in humans. To do this we used a combination of next generation sequencing on engineered model cell lines, in vitro biochemistry and tumor sequencing data from human patients. In MMR-deficient cells, Pol ε exonuclease deficiency causes a large and rapid increase in mutation accumulation, consistent with what has been suggested by Pol ε mutant/MMR-deficient tumors from patients with biallelic mismatch repair deficiency (bMMRD). Restoring MMR suppresses the large mutation rates back to wild type levels. However, Pol ε signature mutations occur even when MMR is functional. These results suggest that the Pol ε exonuclease-deficient replication errors that dominate somatic tumor mutation spectra may accumulate in patients due to their less efficient correction by the endogenous MMR. This further suggests that the Pol ε-dependent mutation accumulation is the driving event in these tumors, with MSI playing little if any role.