Risks at the DNA Replication Fork: Effects upon Carcinogenesis and Tumor Heterogeneity.
Risks at the DNA Replication Fork: Effects upon Carcinogenesis and Tumor Heterogeneity.
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DOI：
10.3390/genes8010046
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发表时间：
2017-01-22
期刊：
影响因子：
3.5
通讯作者：
Roberts SA
中科院分区：
文献类型：
--
作者：
Mertz TM;Harcy V;Roberts SA
所有生物通过DNA复制复制其遗传信息的能力是细胞分裂的先决条件，也是生命的生物学必要条件。然而，在多细胞生物中，生殖细胞和体细胞中DNA复制错误引起的突变分别是遗传疾病和癌症的基础。在人类肿瘤中，复制错误还有助于增变基因表型和肿瘤异质性，这是癌症治疗的主要混杂因素。成功的DNA复制涉及许多大规模、复杂的细胞过程的协调。在这篇综述中，我们关注的作用，通常在复制叉和失调的酶，不适当地损害单链DNA在叉发挥的作用，导致突变，有助于致癌作用的酶的缺陷。我们专注于肿瘤数据和实验证据，复制聚合酶的易错变体促进致癌作用，并研究表明，APOBEC（载脂蛋白B mRNA编辑酶催化多肽样）胞苷脱氨酶突变的主要目标是复制叉处存在的ssDNA。此外，我们还讨论了来自模型系统的证据，这些证据表明复制应激和其他癌症相关的代谢变化可能会调节复制叉处的致突变酶活性。
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.