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Although it has long been recognized that the exonucleolytic proofreading activity intrinsic to the replicative DNA polymerases Pol δ and Pol ε is essential for faithful replication of DNA, evidence that defective DNA polymerase proofreading contributes to human malignancy has been limited. However, recent studies have shown that germline mutations in the proofreading domains of Pol δ and Pol ε predispose to cancer, and that somatic Pol ε proofreading domain mutations occur in multiple sporadic tumours, where they underlie a phenotype of 'ultramutation' and favourable prognosis. In this Review, we summarize the current understanding of the mechanisms and consequences of polymerase proofreading domain mutations in human malignancies, and highlight the potential utility of these variants as novel cancer biomarkers and therapeutic targets.

Original publication




Journal article


Nat Rev Cancer

Publication Date





71 - 81


DNA Polymerase II, DNA Polymerase III, DNA Replication, DNA-Directed DNA Polymerase, Endometrial Neoplasms, Female, Genetic Predisposition to Disease, Humans, Mutation, Neoplasms, Poly-ADP-Ribose Binding Proteins, Prognosis, Saccharomyces cerevisiae