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首页> 外文期刊>Molecular and Cellular Biology >A Single Conserved Residue Mediates Binding of the Ribonucleotide Reductase Catalytic Subunit RRM1 to RRM2 and Is Essential for Mouse Development
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A Single Conserved Residue Mediates Binding of the Ribonucleotide Reductase Catalytic Subunit RRM1 to RRM2 and Is Essential for Mouse Development

机译：一个保守的残基介导核糖核苷酸还原酶催化亚基RRM1到RRM2的结合，是小鼠发育必不可少的

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The ribonucleotide reductase (RNR) complex, composed of a catalytic subunit (RRM1) and a regulatory subunit (RRM2), is thought to be a rate-limiting enzymatic complex for the production of nucleotides. In humans, the Rrm1 gene lies at 11p15.5, a tumor suppressor region, and RRM1 expression in cancer has been shown to predict responses to chemotherapy. Nevertheless, whether RRM1 is essential in mammalian cells and what the effects of its haploinsufficiency are remain unknown. To model RNR function in mice we used a mutation previously described in Saccharomyces cerevisiae (Rnr1-W688G) which, despite being viable, leads to increased interaction of the RNR complex with its allosteric inhibitor Sml1. In contrast to yeast, homozygous mutant mice carrying the Rrm1 mutation (Rrm1WG/WG) are not viable, even at the earliest embryonic stages. Proteomic analyses failed to identify proteins that specifically bind to the mutant RRM1 but revealed that, in mammals, the mutation prevents RRM1 binding to RRM2. Despite the impact of the mutation, Rrm1WG/+ mice and cells presented no obvious phenotype, suggesting that the RRM1 protein exists in excess. Our work reveals that binding of RRM1 to RRM2 is essential for mammalian cells and provides the first loss-of-function model of the RNR complex for genetic studies.
机译：由催化亚基（RRM1​​）和调节亚基（RRM2）组成的核糖核苷酸还原酶（RNR）复合物被认为是核苷酸生产的限速酶复合物。在人类中， Rrm1 基因位于抑癌区域11p15.5，并且已证明癌症中RRM1的表达可预测对化学疗法的反应。尽管如此，RRM1在哺乳动物细胞中是否必不可少以及其单倍剂量不足的作用尚不清楚。为了模拟小鼠中的RNR功能，我们使用了先前在酿酒酵母（Rnr1-W688G）中描述的突变，尽管该突变可行，但会导致RNR复合物与其变构抑制剂Sml1的相互作用增加。与酵母相比，带有 Rrm1 突变（ Rrm1 WG / WG ）的纯合突变小鼠即使在胚胎早期也不能存活。蛋白质组学分析未能鉴定与突变RRM1特异性结合的蛋白质，但揭示了在哺乳动物中，该突变阻止RRM1与RRM2结合。尽管有突变的影响， Rrm1 WG / + 小鼠和细胞没有明显的表型，表明RRM1蛋白过量存在。我们的工作揭示了RRM1与RRM2的结合对于哺乳动物细胞是必不可少的，并为遗传研究提供了RNR复合物的第一个功能丧失模型。

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