期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：17
页码：E1695-E1704
DOI：10.1073/pnas.1405204111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Eukaryotic ribonucleotide reductases (RNRs) require a diferric-tyrosyl radical (FeIII2-Y[bullet]) 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 FeIII2-Y[bullet] cofactor in RNR and the Fe-S clusters in cytosolic and nuclear proteins.
关键词：iron cofactor ; iron regulon ; dNTP pool ; genome stability ; S phase
