Mechanisms of base substitution mutagenesis in cancer genomes.
Mechanisms of base substitution mutagenesis in cancer genomes.
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DOI：
10.3390/genes5010108
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发表时间：
2014-03-05
期刊：
影响因子：
3.5
通讯作者：
Vasquez KM
中科院分区：
文献类型：
--
作者：
Bacolla A;Cooper DN;Vasquez KM
癌症基因组序列数据为推断癌细胞突变的关键机制提供了宝贵的资源，有利于癌细胞的生存，增殖和侵袭。在这里，我们研究了最近的进展，在理解的分子机制，负责在癌细胞中发现的主要类型的遗传改变，体细胞单碱基取代（SBS）。胞嘧啶甲基化、去甲基化和脱氨基化、DNA中的电荷转移反应、DNA复制时间、染色质状态和改变的DNA校正活性现在都已知有助于导致碱基置换诱变的机制。我们回顾目前的假设，引起SBS的主要过程，并评估其相对相关性的知识，从癌症基因组测序项目和碱基修饰，DNA修复和病变旁路的研究。尽管APOBEC3B酶的基因表达数据支持通过U：G错配中间体在癌症诱变中发挥作用，但酶对单链DNA的偏好可能限制其在全基因组范围内的活性。对于在CG：CG和YC：GR网站的SBS，我们概述了一个突出的作用的损害的证据，以下的DNA与活性氧（ROS）和其他内源性或外源性电子提取分子的相互作用的电荷转移反应。
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.
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