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Genes 2017, 8(1), 46; doi:10.3390/genes8010046

Risks at the DNA Replication Fork: Effects upon Carcinogenesis and Tumor Heterogeneity

School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Pullman, WA 99164, USA
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Academic Editor: Eishi Noguchi
Received: 6 December 2016 / Revised: 9 January 2017 / Accepted: 17 January 2017 / Published: 22 January 2017
(This article belongs to the Special Issue DNA Replication Controls)
View Full-Text   |   Download PDF [750 KB, uploaded 22 January 2017]   |  

Abstract

The ability of all organisms to copy their genetic information via DNA replication is a prerequisite for cell division and a biological imperative of life. In multicellular organisms, however, mutations arising from DNA replication errors in the germline and somatic cells are the basis of genetic diseases and cancer, respectively. Within human tumors, replication errors additionally contribute to mutator phenotypes and tumor heterogeneity, which are major confounding factors for cancer therapeutics. Successful DNA replication involves the coordination of many large-scale, complex cellular processes. In this review, we focus on the roles that defects in enzymes that normally act at the replication fork and dysregulation of enzymes that inappropriately damage single-stranded DNA at the fork play in causing mutations that contribute to carcinogenesis. We focus on tumor data and experimental evidence that error-prone variants of replicative polymerases promote carcinogenesis and on research indicating that the primary target mutated by APOBEC (apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like) cytidine deaminases is ssDNA present at the replication fork. Furthermore, we discuss evidence from model systems that indicate replication stress and other cancer-associated metabolic changes may modulate mutagenic enzymatic activities at the replication fork. View Full-Text
Keywords: replication; mutagenesis; cancer; APOBEC; mismatch repair; polymerase delta; polymerase epsilon; replication stress; nucleotide pools replication; mutagenesis; cancer; APOBEC; mismatch repair; polymerase delta; polymerase epsilon; replication stress; nucleotide pools
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Mertz, T.M.; Harcy, V.; Roberts, S.A. Risks at the DNA Replication Fork: Effects upon Carcinogenesis and Tumor Heterogeneity. Genes 2017, 8, 46.

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