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Clb6-Cdc28 Promotes Ribonucleotide Reductase Subcellular Redistribution during S Phase.

Authors
  • Wu, Xiaorong1
  • An, Xiuxiang1
  • Zhang, Caiguo1, 2
  • Huang, Mingxia3, 2
  • 1 Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado, USA.
  • 2 Department of Dermatology, University of Colorado School of Medicine, Aurora, Colorado, USA.
  • 3 Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado, USA [email protected]
Type
Published Article
Journal
Molecular and Cellular Biology
Publisher
American Society for Microbiology
Publication Date
Mar 15, 2018
Volume
38
Issue
6
Identifiers
DOI: 10.1128/MCB.00497-17
PMID: 29263158
Source
Medline
Keywords
License
Unknown

Abstract

A tightly controlled cellular deoxyribonucleotide (deoxynucleoside triphosphate [dNTP]) pool is critical for maintenance of genome integrity. One mode of dNTP pool regulation is through subcellular localization of ribonucleotide reductase (RNR), the enzyme that catalyzes the rate-limiting step of dNTP biosynthesis. In Saccharomyces cerevisiae, the RNR small subunit, Rnr2-Rnr4, is localized to the nucleus, whereas the large subunit, Rnr1, is cytoplasmic. As cells enter S phase or encounter DNA damage, Rnr2-Rnr4 relocalizes to the cytoplasm to form an active holoenzyme complex with Rnr1. Although the DNA damage-induced relocalization requires the checkpoint kinases Mec1-Rad53-Dun1, the S-phase-specific redistribution does not. Here, we report that the S-phase cyclin-cyclin-dependent kinase (CDK) complex Clb6-Cdc28 controls Rnr2-Rnr4 relocalization in S phase. Rnr2 contains a consensus CDK site and exhibits Clb6-dependent phosphorylation in S phase. Deletion of CLB6 or removal of the CDK site results in an increased association of Rnr2 with its nuclear anchor Wtm1, nuclear retention of Rnr2-Rnr4, and an enhanced sensitivity to the RNR inhibitor hydroxyurea. Thus, we propose that Rnr2-Rnr4 redistribution in S phase is triggered by Clb6-Cdc28-mediated phosphorylation of Rnr2, which disrupts the Rnr2-Wtm1 interaction and promotes the release of Rnr2-Rnr4 from the nucleus.

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