文章：

脱氧核糖核苷酸代谢，突变和癌症

Deoxyribonucleotide metabolism, mutagenesis and cancer

原文发布日期：2015-08-24

DOI: 10.1038/nrc3981

类型: Review Article

开放获取: 否

要点：

1. Eukaryotic cells contain two distinct but interrelated pools of DNA precursors for the replication of nuclear and mitochondrial DNA. Deoxyribonucleoside triphosphate (dNTP) biosynthesis begins either with the reduction of ribonucleotides or with the salvage of preformed nucleosides or nucleobases.
2. dNTP pool sizes are regulated mostly at the level of biosynthesis, particularly involving ribonucleotide reductase. However, controlled dNTP degradation brought about by the sterile α-motif and histidine-aspartate domain-containing protein (SAMHD1) protein has recently emerged as a major regulatory mechanism.
3. An increase in the spontaneous mutation rate is almost certainly an essential feature of carcinogenesis. Abnormal regulation of dNTP pool sizes contributes to determination of the mutation rate.
4. Several oncogenes and tumour suppressors control dNTP pool sizes and have as-yet-unexplained effects on oncogene-induced senescence.
5. Much evidence indicates that 'sanitation', the enzymatic hydrolysis of abnormal or damaged nucleotides, is important to the maintenance of genomic stability. However, recent evidence indicates that one sanitizing enzyme, MTH1, is an important target for inhibition in cancer treatment.
6. Many anticancer drugs achieve their effectiveness because they are analogues to DNA precursors. Effective use of these analogues requires a thorough understanding of nucleotide biosynthesis, transport processes, cell cycle regulation and interactions with target enzymes.

要点翻译：

1. 真核细胞含有两个独特但相互关联的DNA前体池，用于核DNA和线粒体DNA的复制。脱氧核糖核苷三磷酸（dNTP）的生物合成起始于核糖核苷酸的还原，或通过预制核苷或碱基的回收利用。
2. dNTP池大小的调控主要发生在生物合成层面，尤其涉及核糖核苷酸还原酶。然而，由无菌α基序和组氨酸-天冬氨酸结构域包含蛋白（SAMHD1）介导的受控dNTP降解，近来已成为重要的调控机制。
3. 自发突变率的增加几乎可以肯定是致癌过程的一个基本特征。dNTP池大小的异常调控对突变率的确定起着重要作用。
4. 若干癌基因和肿瘤抑制因子可调控dNTP池大小，并对癌基因诱导的衰老产生尚未得到解释的影响。
5. 大量证据表明，"清理"过程——即通过酶解作用清除异常或受损核苷酸——对维持基因组稳定性至关重要。然而，最新研究发现其中一种清理酶MTH1已成为癌症治疗中的重要抑制靶点。
6. 许多抗癌药物通过模拟DNA前体来实现其疗效。这类类似物的有效使用需要深入了解核苷酸生物合成、转运过程、细胞周期调控及其与靶酶相互作用机制。

英文摘要：

Cancer was recognized as a genetic disease at least four decades ago, with the realization that the spontaneous mutation rate must increase early in tumorigenesis to account for the many mutations in tumour cells compared with their progenitor pre-malignant cells. Abnormalities in the deoxyribonucleotide pool have long been recognized as determinants of DNA replication fidelity, and hence may contribute to mutagenic processes that are involved in carcinogenesis. In addition, many anticancer agents antagonize deoxyribonucleotide metabolism. Here, we consider the extent to which aspects of deoxyribonucleotide metabolism contribute to our understanding of both carcinogenesis and to the effective use of anticancer agents.

摘要翻译： 

早在四十年前，癌症就被确认为一种遗传性疾病；人们意识到，为了解释肿瘤细胞相比其前恶性祖细胞所携带的大量突变，自发突变率必须在肿瘤发生早期就升高。脱氧核糖核苷酸池的异常早已被认定是决定DNA复制保真度的因素，因此可能参与致癌过程中的致突变作用。此外，许多抗癌药物也拮抗脱氧核糖核苷酸的代谢。本文我们探讨脱氧核糖核苷酸代谢的各个方面在多大程度上加深了我们对致癌机制以及抗癌药物有效应用的理解。

原文链接：

Deoxyribonucleotide metabolism, mutagenesis and cancer