Dyrk2-associated EDD-DDB1-VprBP E3 ligase inhibits telomerase by TERT degradation.
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.
Department of Experimental Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Hae-Yun
HY
Jung
Xin
X
Wang
Sohee
S
Jun
Jae-Il
JI
Park
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016195:G2 Phase; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D061986:MCF-7 Cells; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D034622:RNA Interference; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000097603:Dyrk Kinases
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D019098:Telomerase; D044767:Ubiquitin-Protein Ligases; D000097603:Dyrk Kinases; C091435:DDB1 protein, human; C117617:UBR5 protein, human; C530533:DCAF1 protein, human; C509186:TERT protein, human