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Mechanisms of base substitution mutagenesis in cancer genomes

Bacolla, Albino, Cooper, David Neil ORCID: https://orcid.org/0000-0002-8943-8484 and Vasquez, Karen M. 2014. Mechanisms of base substitution mutagenesis in cancer genomes. Genes 5 (1) , pp. 108-146. 10.3390/genes5010108

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Abstract

Cancer genome sequence data provide an invaluable resource for inferring the key mechanisms by which mutations arise in cancer cells, favoring their survival, proliferation and invasiveness. Here we examine recent advances in understanding the molecular mechanisms responsible for the predominant type of genetic alteration found in cancer cells, somatic single base substitutions (SBSs). Cytosine methylation, demethylation and deamination, charge transfer reactions in DNA, DNA replication timing, chromatin status and altered DNA proofreading activities are all now known to contribute to the mechanisms leading to base substitution mutagenesis. We review current hypotheses as to the major processes that give rise to SBSs and evaluate their relative relevance in the light of knowledge acquired from cancer genome sequencing projects and the study of base modifications, DNA repair and lesion bypass. Although gene expression data on APOBEC3B enzymes provide support for a role in cancer mutagenesis through U:G mismatch intermediates, the enzyme preference for single-stranded DNA may limit its activity genome-wide. For SBSs at both CG:CG and YC:GR sites, we outline evidence for a prominent role of damage by charge transfer reactions that follow interactions of the DNA with reactive oxygen species (ROS) and other endogenous or exogenous electron-abstracting molecules.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Uncontrolled Keywords: genetic alterations; cancer etiology; cancer genomes; functional genomics; human genome sequence; single base substitutions;DNA repair; translesion synthesis; oxidative damage; cytosine deamination
Additional Information: This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Publisher: MDPI
ISSN: 2073-4425
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 11 February 2014
Last Modified: 09 May 2023 18:16
URI: https://orca.cardiff.ac.uk/id/eprint/83908

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