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IRBIT is a novel regulator of ribonucleotide reductase in higher eukaryotes

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Science  19 Sep 2014:
Vol. 345, Issue 6203, pp. 1512-1515
DOI: 10.1126/science.1251550

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Regulating DNA building blocks

The bulding blocks of DNA, deoxynucleotide triphosphates, are synthesized by the enzyme ribonucleotide reductase (RNR). Its central role in DNA synthesis and its aberrant expression in tumors have made it an important anticancer target, but nucleoside analog inhibitors of RNR can have adverse side effects. Arnaoutov and Dasso identify IRBIT (IP3-receptor-binding protein released with inositol 1,4,5-trisphosphate) as an RNR-binding protein. IRBIT regulates the activity of RNR by stabilizing the inactive form bound to deoxyadenosine triphosphate in the low-affinity A site. In turn, phosophorylation of IRBIT regulates its RNR-binding activity. IRBIT provides a new target for RNR inhibition that might avoid some of the side effects of current drugs.

Science, this issue p. 1512

Abstract

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.

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