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Originally published as Genetics Published Articles Ahead of Print on February 19, 2006.
Genetics, Vol. 173, 63-73, May 2006, Copyright © 2006
doi:10.1534/genetics.105.055236
Cotransport of the Heterodimeric Small Subunit of the Saccharomyces cerevisiae Ribonucleotide Reductase Between the Nucleus and the Cytoplasm
Xiuxiang An, Zhen Zhang, Kui Yang and Mingxia Huang1
Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Aurora, Colorado 80045
1 Corresponding author: Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Mail Stop 8101, P.O. Box 6511, Aurora, CO 80045.
E-mail: mingxia.huang{at}uchsc.edu
Ribonucleotide reductase (RNR) catalyzes the rate-liming step in de novo deoxyribonucleotide biosynthesis and is essential in DNA replication and repair. Cells have evolved complex mechanisms to modulate RNR activity during normal cell cycle progression and in response to genotoxic stress. A recently characterized mode of RNR regulation is DNA damage-induced RNR subunit redistribution. The RNR holoenzyme consists of a large subunit, R1, and a small subunit, R2. The Saccharomyces cerevisiae R2 is an Rnr2:Rnr4 heterodimer. Rnr2 generates a diferric–tyrosyl radical cofactor required for catalysis; Rnr4 facilitates cofactor assembly and stabilizes the resulting holo-heterodimer. Upon DNA damage, Rnr2 and Rnr4 undergo checkpoint-dependent, nucleus-to-cytoplasm redistribution, resulting in colocalization of R1 and R2. Here we present evidence that Rnr2 and Rnr4 are transported between the nucleus and the cytoplasm as one protein complex. Tagging either Rnr2 or Rnr4 with a nuclear export sequence causes cytoplasmic localization of both proteins. Moreover, mutations at the Rnr2:Rnr4 heterodimer interface can affect the localization of both proteins without disrupting the heterodimeric complex. Finally, the relocalization of Rnr4 appears to involve both active export and blockage of nuclear import. Our findings provide new insights into the mechanism of DNA damage-induced RNR subunit redistribution.
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