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Nat Rev Cancer. 2016 Feb;16(2):71-81. doi: 10.1038/nrc.2015.12.

A panoply of errors: polymerase proofreading domain mutations in cancer.

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Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Postbus 9600, 2300 RC Leiden, The Netherlands.
Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, UK.


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.

[Indexed for MEDLINE]

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