Conserved electron donor complex Dre2-Tah18 is required for ribonucleotide reductase metallocofactor assembly and DNA synthesis
Name
Zhang-2014-Conserved electron d.pdf
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Author(s)
Zhang, Yan
Li, Haoran
Zhang, Caiguo
An, Xiuxiang
Liu, Lili
Stubbe, JoAnne
Huang, Mingxia
Date Issued
April 2014
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Zhang, Y., H. Li, C. Zhang, X. An, L. Liu, J. Stubbe, and M. Huang. “Conserved Electron Donor Complex Dre2-Tah18 Is Required for Ribonucleotide Reductase Metallocofactor Assembly and DNA Synthesis.” Proceedings of the National Academy of Sciences 111, no. 17 (April 14, 2014): E1695–E1704.
Version
Final published version
Abstract
Eukaryotic ribonucleotide reductases (RNRs) require a diferric-tyrosyl radical (Fe[III over 2]-Y•) cofactor to produce deoxynucleotides essential for DNA replication and repair. This metallocofactor is an important target of RNR-based therapeutics, although mechanisms of in vivo cofactor assembly, inactivation, and reactivation are poorly understood. Here, we demonstrate that the conserved Fe-S protein–diflavin reductase complex, Dre2–Tah18, plays a critical role in RNR cofactor biosynthesis. Depletion of Dre2 affects both RNR gene transcription and mRNA turnover through the activation of the DNA-damage checkpoint and the Aft1/Aft2-controlled iron regulon. Under conditions of comparable RNR protein levels, cells with diminishing Dre2 have significantly reduced ability to make deoxynucleotides. Furthermore, the kinetics and levels of in vivo reconstitution of the RNR cofactor are severely impaired in two conditional tah18 mutants. Together, these findings provide insight into RNR cofactor formation and reveal a shared mechanism underlying assembly of the Fe[III over 2]-Y• cofactor in RNR and the Fe-S clusters in cytosolic and nuclear proteins.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Chemistry
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DOI of Published Version
https://doi.org/10.1073/pnas.1405204111
