Nuclear localization of the <i>Saccharomyces cerevisiae</i> ribonucleotide reductase small subunit requires a karyopherin and a WD40 repeat protein

  • Zhen Zhang
    Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Aurora, CO 80045; Departments of Chemistry and Biology, Massachusetts Institute of Technology, Cambridge, MA 02139; and Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801
  • Xiuxiang An
    Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Aurora, CO 80045; Departments of Chemistry and Biology, Massachusetts Institute of Technology, Cambridge, MA 02139; and Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801
  • Kui Yang
    Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Aurora, CO 80045; Departments of Chemistry and Biology, Massachusetts Institute of Technology, Cambridge, MA 02139; and Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801
  • Deborah L. Perlstein
    Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Aurora, CO 80045; Departments of Chemistry and Biology, Massachusetts Institute of Technology, Cambridge, MA 02139; and Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801
  • Leslie Hicks
    Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Aurora, CO 80045; Departments of Chemistry and Biology, Massachusetts Institute of Technology, Cambridge, MA 02139; and Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801
  • Neil Kelleher
    Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Aurora, CO 80045; Departments of Chemistry and Biology, Massachusetts Institute of Technology, Cambridge, MA 02139; and Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801
  • JoAnne Stubbe
    Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Aurora, CO 80045; Departments of Chemistry and Biology, Massachusetts Institute of Technology, Cambridge, MA 02139; and Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801
  • Mingxia Huang
    Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Aurora, CO 80045; Departments of Chemistry and Biology, Massachusetts Institute of Technology, Cambridge, MA 02139; and Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801

抄録

<jats:p> Ribonucleotide reductase (RNR) catalyzes the reduction of ribonucleotides to the corresponding deoxyribonucleotides and is an essential enzyme for DNA replication and repair. Cells have evolved intricate mechanisms to regulate RNR activity to ensure high fidelity of DNA replication during normal cell-cycle progression and of DNA repair upon genotoxic stress. The RNR holoenzyme is composed of a large subunit R1 (α, oligomeric state unknown) and a small subunit R2 (β <jats:sub>2</jats:sub> ). R1 binds substrates and allosteric effectors; R2 contains a diferric-tyrosyl radical [(Fe) <jats:sub>2</jats:sub> -Y·] cofactor that is required for catalysis. In <jats:italic>Saccharomyces cerevisiae</jats:italic> , R1 is predominantly localized in the cytoplasm, whereas R2, which is a heterodimer (ββ′), is predominantly in the nucleus. When cells encounter DNA damage or stress during replication, ββ′ is redistributed from the nucleus to the cytoplasm in a checkpoint-dependent manner, resulting in the colocalization of R1 and R2. We have identified two proteins that have an important role in ββ′ nuclear localization: the importin β homolog Kap122 and the WD40 repeat protein Wtm1. Deletion of either <jats:italic>WTM1</jats:italic> or <jats:italic>KAP122</jats:italic> leads to loss of ββ′ nuclear localization. Wtm1 and its paralog Wtm2 are both nuclear proteins that are in the same protein complex with ββ′. Wtm1 also interacts with Kap122 <jats:italic>in vivo</jats:italic> and requires Kap122 for its nuclear localization. Our results suggest that Wtm1 acts either as an adaptor to facilitate nuclear import of ββ′ by Kap122 or as an anchor to retain ββ′ in the nucleus. </jats:p>

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