title: Replicative DNA polymerase mutations in cancer.
abstract: Three DNA polymerases - Pol α, Pol δ and Pol ɛ - are essential for DNA replication. After initiation of DNA synthesis by Pol α, Pol δ or Pol ɛ take over on the lagging and leading strand respectively. Pol δ and Pol ɛ perform the bulk of replication with very high fidelity, which is ensured by Watson-Crick base pairing and 3'exonuclease (proofreading) activity. Yeast models have shown that mutations in the exonuclease domain of Pol δ and Pol ɛ homologues can cause a mutator phenotype. Recently, we identified germline exonuclease domain mutations (EDMs) in human POLD1 and POLE that predispose to 'polymerase proofreading associated polyposis' (PPAP), a disease characterised by multiple colorectal adenomas and carcinoma, with high penetrance and dominant inheritance. Moreover, somatic EDMs in POLE have also been found in sporadic colorectal and endometrial cancers. Tumors with EDMs are microsatellite stable and show an 'ultramutator' phenotype, with a dramatic increase in base substitutions.
authors.affiliation: Institute of Human Genetics, Medical University of Graz, Harrachgasse 21/8, A-8010 Graz, Austria. Electronic address: ellen.heitzer@medunigraz.at.
authors.forename: Ellen
authors.initials: E
authors.lastname: Heitzer
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK; Oxford NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK. Electronic address: iant@well.ox.ac.uk.
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
mesh_terms: D000818:Animals; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D010641:Phenotype
chemical_list: D004259:DNA-Directed DNA Polymerase