Title: POLE proofreading defects: Contributions to mutagenesis and cancer.

Authors: Park, Vivian S; Pursell, Zachary F

Published In DNA Repair (Amst), (2019 04)

Abstract: DNA polymerases are uniquely poised to contribute to the elevated mutation burdens seen in many human tumors. These mutations can arise through a number of different polymerase-dependent mechanisms, including intrinsic errors made using template DNA and precursor dNTPs free from chemical modifications, misinsertion events opposite chemically damaged template DNA or insertion events using modified nucleotides. While specific DNA repair polymerases have been known to contribute to tumorigenesis, the role of replication polymerases in mutagenesis in human disease has come into sharp focus over the last decade. This review describes how mutations in these replication DNA polymerases help to drive mutagenesis and tumor development, with particular attention to DNA polymerase epsilon. Recent studies using cancer genome sequencing, mutational signature analyses, yeast and mouse models, and the influence of mismatch repair on tumors with DNA polymerase mutations are discussed.

PubMed ID: 30818169

MeSH Terms: Animals; Carcinogenesis/genetics; DNA Repair; DNA-Directed DNA Polymerase/metabolism*; Genomic Instability; Humans; Mutagenesis*; Neoplasms/enzymology*; Neoplasms/genetics*; Neoplasms/pathology