IRBIT is a novel regulator of ribonucleotide reductase in higher eukaryotes

被引：41

作者：

Arnaoutov, Alexei ^{[1
]}

Dasso, Mary ^{[1
]}

机构：

[1] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA

来源：

SCIENCE | 2014年 / 345卷 / 6203期

关键词：

ALLOSTERIC REGULATION; INDUCED OLIGOMERIZATION; COMPREHENSIVE MODEL; STRUCTURAL BASIS; BINDING; CONSEQUENCES; INHIBITOR; RECEPTOR; SML1;

D O I：

10.1126/science.1251550

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Ribonucleotide reductase (RNR) supplies the balanced pools of deoxynucleotide triphosphates (dNTPs) necessary for DNA replication and maintenance of genomic integrity. RNR is subject to allosteric regulatory mechanisms in all eukaryotes, as well as to control by small protein inhibitors Sml1p and Spd1p in budding and fission yeast, respectively. Here, we show that the metazoan protein IRBIT forms a deoxyadenosine triphosphate (dATP)-dependent complex with RNR, which stabilizes dATP in the activity site of RNR and thus inhibits the enzyme. Formation of the RNR-IRBIT complex is regulated through phosphorylation of IRBIT, and ablation of IRBIT expression in HeLa cells causes imbalanced dNTP pools and altered cell cycle progression. We demonstrate a mechanism for RNR regulation in higher eukaryotes that acts by enhancing allosteric RNR inhibition by dATP.

引用

页码：1512 / 1515

页数：4

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