Aye Y, Li M, Long M J C, Weiss R S
1] Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA [2] Department of Biochemistry, Weill Cornell Medical College, New York, NY, USA.
Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA.
Oncogene. 2015 Apr 16;34(16):2011-21. doi: 10.1038/onc.2014.155. Epub 2014 Jun 9.
Accurate DNA replication and repair is essential for proper development, growth and tumor-free survival in all multicellular organisms. A key requirement for the maintenance of genomic integrity is the availability of adequate and balanced pools of deoxyribonucleoside triphosphates (dNTPs), the building blocks of DNA. Notably, dNTP pool alterations lead to genomic instability and have been linked to multiple human diseases, including mitochondrial disorders, susceptibility to viral infection and cancer. In this review, we discuss how a key regulator of dNTP biosynthesis in mammals, the enzyme ribonucleotide reductase (RNR), impacts cancer susceptibility and serves as a target for anti-cancer therapies. Because RNR-regulated dNTP production can influence DNA replication fidelity while also supporting genome-protecting DNA repair, RNR has complex and stage-specific roles in carcinogenesis. Nevertheless, cancer cells are dependent on RNR for de novo dNTP biosynthesis. Therefore, elevated RNR expression is a characteristic of many cancers, and an array of mechanistically distinct RNR inhibitors serve as effective agents for cancer treatment. The dNTP metabolism machinery, including RNR, has been exploited for therapeutic benefit for decades and remains an important target for cancer drug development.
准确的DNA复制和修复对于所有多细胞生物的正常发育、生长以及无肿瘤生存至关重要。维持基因组完整性的一个关键要求是要有充足且平衡的脱氧核糖核苷三磷酸（dNTP）库，dNTP是DNA的组成成分。值得注意的是，dNTP库的改变会导致基因组不稳定，并与多种人类疾病相关，包括线粒体疾病、病毒感染易感性和癌症。在本综述中，我们讨论了哺乳动物中dNTP生物合成的关键调节因子——核糖核苷酸还原酶（RNR）如何影响癌症易感性，并作为抗癌治疗的靶点。由于RNR调节的dNTP产生既能影响DNA复制保真度，又能支持保护基因组的DNA修复，因此RNR在致癌过程中具有复杂且阶段特异性的作用。然而，癌细胞依赖RNR进行从头合成dNTP。因此，RNR表达升高是许多癌症的一个特征，一系列机制不同的RNR抑制剂可作为有效的癌症治疗药物。包括RNR在内的dNTP代谢机制已被用于治疗益处数十年，并且仍然是癌症药物开发的重要靶点。
