Although the proofreading activity of the lagging strand replicative polymerase Pol δ can also act on the leading strand and correct excessive errors generated by mutated Pol ε (Fig 1) (Bulock et al, 2020), a high increase in mutation rates has been documented in cancers with P286R, D275V, P286H, F367S, L424V, P436R, and S459F changes located closed to the DNA binding cleft of Pol ε (Cancer Genome Atlas Network, 2012; Cancer Genome Atlas Research Network et al, 2013; Kane & Shcherbakova, 2014; Shinbrot et al, 2014; Barbari et al, 2018). Here, EPX is linked to cancer.