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doi:10.1534/genetics.105.055236
A more recent version of this article appeared on May 1, 2006.
REGULAR RESEARCH PAPERS |
Co-transport of the Heterodimeric Small Subunit of the S. cerevisiae Ribonucleotide Reductase between the Nucleus and the Cytoplasm
Xiuxiang An 1, Zhen Zhang 1, Kui Yang 1 and Mingxia Huang 1*
1 University of Colorado Health Sciences Cetner
* To whom correspondence should be addressed. E-mail: mingxia.huang{at}uchsc.edu.
Submitted on December 28, 2005
Revised on February 13, 2006
Accepted on 13 February 2006
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 S. cerevisiae R2 is a 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 co-localization 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 cause 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 re-localization 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.
Key Words: DNA damage checkpoint, dNTP, nucleocytoplasmic transport, ribonucleotide reductase
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