Regulation of ribonucleotide reductase by Spd1 involves multiple mechanisms

TY - JOUR

T1 - Regulation of ribonucleotide reductase by Spd1 involves multiple mechanisms

AU - Nestoras, Konstantinos

AU - Mohammed, Asma Hadi

AU - Schreurs, Ann-Sofie

AU - Fleck, Oliver

AU - Watson, Adam T

AU - Poitelea, Marius

AU - O'Shea, Charlotte

AU - Chahwan, Charly

AU - Holmberg, Christian

AU - Kragelund, Birthe B

AU - Nielsen, Olaf

AU - Osborne, Mark

AU - Carr, Antony M

AU - Liu, Cong

PY - 2010/6/1

Y1 - 2010/6/1

N2 - 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.

AB - 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.

KW - Active Transport, Cell Nucleus

KW - Alanine

KW - Cell Cycle Proteins

KW - Gene Expression Regulation, Fungal

KW - Mutagenesis

KW - Protein Subunits

KW - Ribonucleotide Reductases

KW - Schizosaccharomyces

KW - Schizosaccharomyces pombe Proteins

U2 - 10.1101/gad.561910

DO - 10.1101/gad.561910

M3 - Journal article

C2 - 20516199

SN - 0890-9369

VL - 24

SP - 1145

EP - 1159

JO - Genes & Development

JF - Genes & Development

IS - 11

ER -