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.
Highlights
The explosion of cancer genome sequencing projects over the past few years has revealed the complexity of the processes whose alterations are associated with, and are often causative of, various types of cancer [1,2]
MRNA; APOBEC2, which is expressed in heart and skeletal muscles and which appears to be essential for muscle development; APOBEC3s (A, B, C, D, F, G and H), which are active against exogenous viruses and endogenous retroelements and important for innate immunity; and APOBEC4, which is mostly expressed in the testes but whose function remains unknown [63]
Substrates at TC:GA dinucleotides when treated with a control shRNA, whereas no activity was evident upon treatment with short hairpin RNA targeting APOBEC3B mRNA
Summary
The explosion of cancer genome sequencing projects over the past few years has revealed the complexity of the processes whose alterations are associated with, and are often causative of, various types of cancer [1,2] These include mutational mechanisms that give rise to tissue-specific mutation rates, variations in mutation frequencies in distinct compartments of chromosomes, sequence context-dependent mutation spectra, and regional hypermutation, often termed kataegis (thunderstorm) [3]. Attempts to address key questions concerning the causes leading to the mutational events that characterize and contribute to driving a normal cell towards tumorigenesis have burgeoned [12,13,14] These attempts are, necessarily indirect since the only material available for analysis are the catalogues of mutations that survived and accumulated, in most cases, over long periods of time. After considering several factors associated with SBSs, such as regional variations in mutation frequencies, mechanisms leading to base modification, and DNA repair systems, we conclude that for both SBS patterns, oxidative base damage from ROS and other electron-abstracting molecules appears to play a more significant role than previously anticipated
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