Regulation of ribonucleotide reductase by Spd1 involves multiple mechanisms
- Konstantinos Nestoras1,
- Asma Hadi Mohammed2,6,
- Ann-Sofie Schreurs1,6,
- Oliver Fleck3,
- Adam T. Watson1,
- Marius Poitelea1,
- Charlotte O'Shea4,
- Charly Chahwan5,
- Christian Holmberg3,
- Birthe B. Kragelund4,
- Olaf Nielsen3,
- Mark Osborne2,
- Antony M. Carr1,7 and
- Cong Liu1
- 1Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton BN1 9RQ, United Kingdom;
- 2Department of Chemistry, School of Life Sciences, University of Sussex, Brighton BN1 9RJ, United Kingdom;
- 3Department of Biology, University of Copenhagen, DK-2200 Copenhagen, Denmark;
- 4Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, DK-2200 Copenhagen, Denmark;
- 5Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada
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↵6 These authors contributed equally to this work.
Abstract
The correct levels of deoxyribonucleotide triphosphates and their relative abundance are important to maintain genomic integrity. Ribonucleotide reductase (RNR) regulation is complex and multifaceted. RNR is regulated allosterically by two nucleotide-binding sites, by transcriptional control, and by small inhibitory proteins that associate with the R1 catalytic subunit. In addition, the subcellular localization of the R2 subunit is regulated through the cell cycle and in response to DNA damage. We show that the fission yeast small RNR inhibitor Spd1 is intrinsically disordered and regulates R2 nuclear import, as predicted by its relationship to Saccharomyces cerevisiae Dif1. We demonstrate that Spd1 can interact with both R1 and R2, and show that the major restraint of RNR in vivo by Spd1 is unrelated to R2 subcellular localization. Finally, we identify a new behavior for RNR complexes that potentially provides yet another mechanism to regulate dNTP synthesis via modulation of RNR complex architecture.
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Footnotes
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↵7 Corresponding author.
E-MAIL a.m.carr{at}sussex.ac.uk; FAX: 44-1273-678121.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.561910.
- Received October 9, 2009.
- Accepted April 7, 2010.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press