Dyrk2-associated EDD-DDB1-VprBP E3 ligase inhibits telomerase by TERT degradation

J Biol Chem. 2013 Mar 8;288(10):7252-62. doi: 10.1074/jbc.M112.416792. Epub 2013 Jan 28.

Abstract

Telomerase maintains the telomere, a specialized chromosomal end structure that is essential for genomic stability and cell immortalization. Telomerase is not active in most somatic cells, but its reactivation is one of the hallmarks of cancer. In this study, we found that dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 2 (Dyrk2) negatively regulates telomerase activity. Dyrk2 phosphorylates TERT protein, a catalytic subunit of telomerase. Phosphorylated TERT is then associated with the EDD-DDB1-VprBP E3 ligase complex for subsequent ubiquitin-mediated TERT protein degradation. During the cell cycle, Dyrk2 interacts with TERT at the G2/M phase and induces degradation. In contrast, depletion of endogenous Dyrk2 disrupts the cell cycle-dependent regulation of TERT and elicits the constitutive activation of telomerase. Similarly, a Dyrk2 nonsense mutation identified in breast cancer compromises ubiquitination-mediated TERT protein degradation. Our findings suggest the novel molecular mechanism of kinase-associated telomerase regulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Division
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • G2 Phase
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Immunoblotting
  • MCF-7 Cells
  • Mice
  • Models, Biological
  • Mutation
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Phosphorylation
  • Protein Binding
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Proteolysis
  • RNA Interference
  • Telomerase / genetics
  • Telomerase / metabolism*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination

Substances

  • Carrier Proteins
  • DDB1 protein, human
  • DNA-Binding Proteins
  • UBR5 protein, human
  • Ubiquitin-Protein Ligases
  • Dyrk kinase
  • Protein-Tyrosine Kinases
  • DCAF1 protein, human
  • Protein-Serine-Threonine Kinases
  • TERT protein, human
  • Telomerase