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Download or read book Control of Ribonucleotide Reductase Subcellular Localization by Cell Cycle and DNA Damage Checkpoint written by and published by . This book was released on 2011 with total page 262 pages. Available in PDF, EPUB and Kindle. Book excerpt: "Ribonucleotide reductase (RNR) catalyzes the reduction of NDPs to its corresponding dNDPs. Because of its key role in the synthesis of dNTP, RNR is tightly regulated to ensure the fidelity of DNA replication and DNA repair. One mode of RNR regulation is through subcellular localization of RNR. In S. cerevisiae and S. pombe, the large subunit R1 is predominantly cytoplasmic, whereas the small subunit R2 is nuclear. During S phase of the cell cycleand in response to DNA damage, R2 is redistributed from the nucleus into the cytoplasm to form holoenzyme with cytoplasmic R1. The first direction of my study aimed to identify the role of Dif1 in RNR regulation. I found that Dif1 is a negative regulator of RNR and is required to maintain the proper nuclear localization of R2. Instead anchoring R2 in the nucleus, Dif1 facilitates nuclear import of R2 from the cytoplasm. My next direction of study sought to determine the mechanistic basis of how Dif1 regulates R2 localization in response to DNA damage and replication blockage. I showed that Dif1 is phosphorylated and degraded upon genotoxic stress in a DNA damage checkpoint dependent manner. I also identified three serine/threonine residues in the conserved region between Dif1 and Sml1 that are responsible for Dif1 phosphorylation and degradation in response to DNA damage and replication blockage. The third direction of my study is to investigate how S phase specific localization change of R2 is regulated. I showed that S phase specific R2 redistribution is independent on DNA damage checkpoint but dependent on cell cycle kinases CDK. I demonstrated that S phase specific phosphorylation of R2 by Cdc28/Clb6 disrupts the interaction between R2 and Wtm1, which leads to the release of R2 from the nucleus into the cytoplasm. These findings provide new insights into the regulation of R2 localization by cell cycle and DNA damage."--Abstract.