Department of Biotechnology, Institute of Agrochemistry and Food Technology, Spanish Research Council, Valencia, E-46980, Spain.
Biomed J. 2013 Mar-Apr;36(2):51-8. doi: 10.4103/2319-4170.110398.
Ribonucleotide reductases (RNRs) are essential enzymes that catalyze the reduction of ribonucleotides to desoxyribonucleotides, thereby providing the building blocks required for de novo DNA biosynthesis. The RNR function is tightly regulated because an unbalanced or excessive supply of deoxyribonucleoside triphosphates (dNTPs) dramatically increases the mutation rates during DNA replication and repair that can lead to cell death or genetic anomalies. In this review, we focus on Saccharomyces cerevisiae class Ia RNR as a model to understand the different mechanisms controlling RNR function and regulation in eukaryotes. Many studies have contributed to our current understanding of RNR allosteric regulation and, more recently, to its link to RNR oligomerization. Cells have developed additional mechanisms that restrict RNR activity to particular periods when dNTPs are necessary, such as the S phase or upon genotoxic stress. These regulatory strategies include the transcriptional control of the RNR gene expression, inhibition of RNR catalytic activity, and the subcellular redistribution of RNR subunits. Despite class Ia RNRs requiring iron as an essential cofactor for catalysis, little is known about RNR function regulation depending on iron bioavailability. Recent studies into yeast have deciphered novel strategies for the delivery of iron to RNR and for its regulation in response to iron deficiency. Taken together, these studies open up new possibilities to explore in order to limit uncontrolled tumor cell proliferation via RNR.
核糖核苷酸还原酶（RNRs）是催化核糖核苷酸还原为脱氧核糖核苷酸的必需酶，从而为从头合成 DNA 提供所需的构建块。RNR 的功能受到严格调控，因为不平衡或过量的脱氧核苷三磷酸（dNTPs）供应会在 DNA 复制和修复过程中大大增加突变率，从而导致细胞死亡或遗传异常。在这篇综述中，我们以酿酒酵母 Ia 类 RNR 为模型，重点研究了真核生物中控制 RNR 功能和调节的不同机制。许多研究有助于我们当前对 RNR 变构调节的理解，以及最近对其与 RNR 寡聚化的联系的理解。细胞已经开发出了其他机制，将 RNR 活性限制在特定的时期，例如 S 期或在遗传毒性应激时，此时需要 dNTPs。这些调控策略包括 RNR 基因表达的转录控制、抑制 RNR 催化活性以及 RNR 亚基的亚细胞重新分布。尽管 Ia 类 RNR 需要铁作为催化所必需的辅助因子，但对于依赖铁生物利用度的 RNR 功能调节知之甚少。最近对酵母的研究揭示了向 RNR 输送铁并响应铁缺乏进行调节的新策略。总之，这些研究为通过 RNR 限制不受控制的肿瘤细胞增殖开辟了新的探索可能性。
