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.
Nat Rev Cancer. 2016 Feb;16(2):71-81. doi: 10.1038/nrc.2015.12.
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.
尽管长期以来人们一直认识到，复制 DNA 聚合酶 Pol δ 和 Pol ε 固有的外切核酸酶校对活性对于 DNA 的忠实复制至关重要，但证明 DNA 聚合酶校对缺陷导致人类恶性肿瘤的证据有限。然而，最近的研究表明，Pol δ 和 Pol ε 的校对结构域中的种系突变易导致癌症，并且体细胞 Pol ε 校对结构域突变发生在多种散发性肿瘤中，这些突变导致了“超突变”和有利的预后表型。在这篇综述中，我们总结了目前对人类恶性肿瘤中聚合酶校对结构域突变的机制和后果的理解，并强调了这些变体作为新型癌症生物标志物和治疗靶点的潜在用途。
