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A panoply of errors: polymerase proofreading domain mutations in cancer

2016; Nature Portfolio; Volume: 16; Issue: 2 Linguagem: Inglês

10.1038/nrc.2015.12

1474-1768

Emily Rayner, Inge C. van Gool, Claire Palles, Stephen Kearsey, Tjalling Bosse, Ian Tomlinson, David N. Church,

Genetic factors in colorectal cancer

Recent studies have shown that germline and somatic mutations in the proofreading exonuclease domains of the replicative DNA polymerases Pol δ and Pol ε are associated with several cancers. This Review summarizes what these mutations are and how they might drive tumorigenesis, and highlights their potential as novel biomarkers and therapeutic targets. 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.