EPX and cancer: These findings are in line with previous studies of pol2-P301R, pol2-L439V, pol2-V426L and pol2-D290V cells using classical mutation rate assays (31), and together with our results show that ultra-mutagenesis—the accumulation of considerably more mutations than would be expected by loss of exonuclease activity—is a common outcome for mutations in the proofreading domain of Pol ε that are found in cancers.