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.
Highlights
Telomerase is an essential enzyme for the immortalization of stem and cancer cells
dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 2 (Dyrk2)-induced telomerase reverse transcriptase (TERT) Ubiquitination and Degradation—To understand the regulatory mechanism of telomerase, we first compared the level of TERT mRNA transcript with telomerase activity in various cells, including human embryonic stem cells, mouse embryonic stem cells, mouse embryonic fibroblasts, and HeLa cells
The genetic mutation in Dyrk2 identified in breast cancer cells fails to elicit TERT protein degradation, implying that Dyrk2 mutation-induced telomerase deregulation may contribute to tumorigenesis (Fig. 6)
Summary
Telomerase is an essential enzyme for the immortalization of stem and cancer cells. Results: Dyrk2-associated E3 ligase targets telomerase reverse transcriptase, a catalytic subunit of telomerase. We found that dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 2 (Dyrk2) negatively regulates telomerase activity. Dyrk phosphorylates TERT protein, a catalytic subunit of telomerase. The absence of telomerase results in the gradual loss of telomeric repeats with every cell division, which is referred to as a telomere crisis. Recent studies have shown that Wnt/catenin signaling participates in transactivating TERT in cancer and stem cells [18, 19], highlighting the importance of the regulatory mechanism of TERT in controlling telomerase activity. We found that the dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 2 (Dyrk2)-associated E3 ligase complex is involved in degradation of TERT protein and subsequent inhibition of telomerase activity
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