Enzyme Regulation. IRBIT is a Novel Regulator of Ribonucleotide Reductase in Higher Eukaryotes

Overview

Journal Science

Specialty Science

Date 2014 Sep 20

PMID 25237103

Citations 32

Authors

Alexei Arnaoutov

Mary Dasso

Affiliations

Soon will be listed here.

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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References

Yang D, Shcheynikov N, Zeng W, Ohana E, So I, Ando H . IRBIT coordinates epithelial fluid and HCO3- secretion by stimulating the transporters pNBC1 and CFTR in the murine pancreatic duct. J Clin Invest. 2008; 119(1):193-202. PMC: 2613461. DOI: 10.1172/JCI36983. View

Kiefer H, Mizutani A, Iemura S, Natsume T, Ando H, Kuroda Y . Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation. J Biol Chem. 2009; 284(16):10694-705. PMC: 2667756. DOI: 10.1074/jbc.M807136200. View

Shao J, Zhou B, Chu B, Yen Y . Ribonucleotide reductase inhibitors and future drug design. Curr Cancer Drug Targets. 2006; 6(5):409-31. DOI: 10.2174/156800906777723949. View

Cooper B, Key B, Carter A, Angel N, Hart D, Kato M . Suppression and overexpression of adenosylhomocysteine hydrolase-like protein 1 (AHCYL1) influences zebrafish embryo development: a possible role for AHCYL1 in inositol phospholipid signaling. J Biol Chem. 2006; 281(32):22471-84. DOI: 10.1074/jbc.M602520200. View

Ahmad M, Dealwis C . The structural basis for the allosteric regulation of ribonucleotide reductase. Prog Mol Biol Transl Sci. 2013; 117:389-410. PMC: 4059395. DOI: 10.1016/B978-0-12-386931-9.00014-3. View

Wash R, Calabressi S, Franz S, Griffiths S, Goulding D, Tan E . Permissive and restricted virus infection of murine embryonic stem cells. J Gen Virol. 2012; 93(Pt 10):2118-2130. PMC: 3541792. DOI: 10.1099/vir.0.043406-0. View

Fairman J, Wijerathna S, Ahmad M, Xu H, Nakano R, Jha S . Structural basis for allosteric regulation of human ribonucleotide reductase by nucleotide-induced oligomerization. Nat Struct Mol Biol. 2011; 18(3):316-22. PMC: 3101628. DOI: 10.1038/nsmb.2007. View

Tompa P . Intrinsically unstructured proteins. Trends Biochem Sci. 2002; 27(10):527-33. DOI: 10.1016/s0968-0004(02)02169-2. View

Danielsson J, Liljedahl L, Barany-Wallje E, Sonderby P, Kristensen L, Martinez-Yamout M . The intrinsically disordered RNR inhibitor Sml1 is a dynamic dimer. Biochemistry. 2008; 47(50):13428-37. PMC: 2747730. DOI: 10.1021/bi801040b. View

10.

Ahluwalia D, Schaaper R . Hypermutability and error catastrophe due to defects in ribonucleotide reductase. Proc Natl Acad Sci U S A. 2013; 110(46):18596-601. PMC: 3832021. DOI: 10.1073/pnas.1310849110. View

11.

Ormo M, SJOBERG B . An ultrafiltration assay for nucleotide binding to ribonucleotide reductase. Anal Biochem. 1990; 189(1):138-41. DOI: 10.1016/0003-2697(90)90059-i. View

12.

Wijerathna S, Ahmad M, Xu H, Fairman J, Zhang A, Kaushal P . Targeting the Large Subunit of Human Ribonucleotide Reductase for Cancer Chemotherapy. Pharmaceuticals (Basel). 2012; 4(10):1328-1354. PMC: 3483043. DOI: 10.3390/ph4101328. View

13.

Kashlan O, Scott C, Lear J, Cooperman B . A comprehensive model for the allosteric regulation of mammalian ribonucleotide reductase. Functional consequences of ATP- and dATP-induced oligomerization of the large subunit. Biochemistry. 2002; 41(2):462-74. DOI: 10.1021/bi011653a. View

14.

Jordan A, REICHARD P . Ribonucleotide reductases. Annu Rev Biochem. 1998; 67:71-98. DOI: 10.1146/annurev.biochem.67.1.71. View

15.

Chabes A, Domkin V, Thelander L . Yeast Sml1, a protein inhibitor of ribonucleotide reductase. J Biol Chem. 1999; 274(51):36679-83. DOI: 10.1074/jbc.274.51.36679. View

16.

Ando H, Mizutani A, Kiefer H, Tsuzurugi D, Michikawa T, Mikoshiba K . IRBIT suppresses IP3 receptor activity by competing with IP3 for the common binding site on the IP3 receptor. Mol Cell. 2006; 22(6):795-806. DOI: 10.1016/j.molcel.2006.05.017. View

17.

Kashlan O, Cooperman B . Comprehensive model for allosteric regulation of mammalian ribonucleotide reductase: refinements and consequences. Biochemistry. 2003; 42(6):1696-706. DOI: 10.1021/bi020634d. View

18.

REICHARD P, Eliasson R, Ingemarson R, Thelander L . Cross-talk between the allosteric effector-binding sites in mouse ribonucleotide reductase. J Biol Chem. 2000; 275(42):33021-6. DOI: 10.1074/jbc.M005337200. View

19.

Traut T . Physiological concentrations of purines and pyrimidines. Mol Cell Biochem. 1994; 140(1):1-22. DOI: 10.1007/BF00928361. View