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: Ellen Heitzer, Ian Tomlinson
• Journal: Current opinion in genetics & development (Curr Opin Genet Dev) Vol. 24 Pg. 107-13 (Feb 2014) ISSN: 1879-0380 [Electronic] England
• PMID: 24583393 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

• DNA-Directed DNA Polymerase

Topics

• Animals
• DNA-Directed DNA Polymerase (genetics)
• Humans
• Mutation
• Neoplasms (genetics)
• Phenotype