Dyrk2-associated EDD-DDB1-VprBP E3 Ligase Inhibits Telomerase by TERT Degradation

Jung, Hae-Yun; Wang, Xin A.; Jun, Suckjoon; Park, Jae-Il

doi:10.1074/jbc.m112.416792

Cited by 58 publications

(65 citation statements)

References 57 publications

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“…Akt and PKC have been shown to phosphorylate hTERT and enhance telomerase activity (29,30). In contrast, Dyrk2 could phosphorylate TERT, promote its degradation, and subsequently inhibit the telomerase activity (31). Tyrosine kinase c-Abl inhibits telomerase activity by phosphorylating hTERT (32).…”

Section: Discussionmentioning

confidence: 99%

Polo-like Kinase 1 (Plk1) Up-regulates Telomerase Activity by Affecting Human Telomerase Reverse Transcriptase (hTERT) Stability

Huang

Sun

Liu

et al. 2015

Journal of Biological Chemistry

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Background: hTERT plays a central role for telomerase activity and telomeric chromatin maintenance. Results: Plk1 interacts with hTERT and regulates its stability. Overexpression of Plk1 up-regulates the activity of telomerase. Plk1 enhances the chromatin loading of hTERT and inhibits its ubiquitination. Conclusion: Plk1 is a positive regulator of telomerase. Significance: We revealed the mechanism of Plk1 regulating the telomerase activity by stabilizing hTERT protein.

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Section: Discussionmentioning

confidence: 99%

Polo-like Kinase 1 (Plk1) Up-regulates Telomerase Activity by Affecting Human Telomerase Reverse Transcriptase (hTERT) Stability

Huang

Sun

Liu

et al. 2015

Journal of Biological Chemistry

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“…[8][9][10]25 Most importantly, DYRK2 functions as a priming kinase for GSK3 and the SCF complex in G1 phase, because c-Jun and c-Myc degradation is essential for G1/S transition (Fig. 1).…”

Section: Conclusion and Future Prospectsmentioning

confidence: 99%

“…2, upper). 10 Because high telomerase activity is a hallmark of cancer, TERT degradation is one of the tumor suppressive functions of DYRK2. Katanin p60 is a microtubule-severing enzyme that contributes to mitotic spindle formation.…”

Section: Promoting G2/m Transition With Edvp E3 Ligase Complexmentioning

confidence: 99%

Engagement of DYRK2 in proper control for cell division

Nihira

Yoshida

2015

Cell Cycle

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Dysregulation of cell cycle machinery causes abnormal cell division, leading to cancer development. To drive cell cycle properly, expression levels of cell cycle regulators are tightly regulated through the cell cycle. Dual specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) is a Ser/Thr kinase, and its intracellular functions had not been elucidated for decades. Recent studies have shown that DYRK2 downregulates key molecules on cell cycle control. This review mainly highlights the DYRK2 function during cell division. In addition, we summarize tumor suppressive role of DYRK2 in cancer cells and discuss future research directions for DYRK2 toward the novel cancer therapies.

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“…UBR5 also has E3-independent roles as a transcriptional cofactor for the progesterone receptor (13) and interacts with other proteins such as p53 (14). UBR5 has been shown to mediate degradation of several proteins, including katanin p60, beta-catenin, TOPBP1, and TERT protein, the catalytic subunit of telomerase (15)(16)(17)(18). UBR5 has also been implicated in the DNA damage response: it interacts with Chk2 and is necessary for Chk2 phosphorylation and cellcycle arrest in response to IR (19,20).…”

mentioning

confidence: 99%

UBR5-mediated ubiquitination of ATMIN is required for ionizing radiation-induced ATM signaling and function

Zhang

Cronshaw

Kanu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The Mre11/Rad50/NBS1 (MRN) protein complex and ATMIN protein mediate ATM kinase signaling in response to ionizing radiation (IR) and chromatin changes, respectively. NBS1 and ATMIN directly compete for ATM binding, but the molecular mechanism favoring either NBS1 or ATMIN in response to specific stimuli is enigmatic. Here, we identify the E3 ubiquitin ligase UBR5 as a key component of ATM activation in response to IR. UBR5 interacts with ATMIN and catalyzes ubiquitination of ATMIN at lysine 238 in an IR-stimulated manner, which decreases ATMIN interaction with ATM and promotes MRN-mediated signaling. We show that UBR5 deficiency, or mutation of ATMIN lysine 238, prevents ATMIN dissociation from ATM and inhibits ATM and NBS1 foci formation after IR, thereby impairing checkpoint activation and increasing radiosensitivity. Thus, UBR5-mediated ATMIN ubiquitination is a vital event for ATM pathway selection and activation in response to DNA damage.A TM kinase is part of the phosphatidylinositol 3-kinaserelated kinase (PIKK) family that activates cell-cycle checkpoints and promotes DNA repair in response to DNA damage or replication blocks (1). Mutation of ATM causes the genomic instability syndrome ataxia telangiectasia, characterized by cerebellar degeneration, immunodeficiency, and increased tumor incidence (2).In response to DNA double-strand breaks (DSBs), inactive ATM homodimers dissociate and the kinase is activated (3), phosphorylating other ATM molecules, as well as numerous substrates including structural maintenance of chromosomes protein 1 (SMC1) and p53, at serine or threonine residues followed by glutamine (the "SQ/TQ" motif) (4, 5). ATM is activated at DSB sites via the Mre11/Rad50/NBS1 (MRN) complex, which is required for ATM activation and recruitment into nuclear foci, and MRN interacts with ATM mainly via its NBS1 subunit (6, 7). A short C-terminal motif in NBS1 principally contributes to ATM binding (8), and the interaction is also strengthened by ubiquitination of NBS1 (9).ATM not only is central to the DSB response but also responds to many other cellular stresses, such as UV damage and hypotonic stress (1, 3). In contrast to its role at DSB sites, NBS1 is not required for ATM activation by these stimuli (10, 11); instead, ATM is activated via interaction with its cofactor ATMIN (12). Accordingly, ATMIN colocalizes with phosphorylated ATM in basal conditions and after hypotonic stress, but not after ionizing radiation (IR). The mechanism of the switch between these different signaling conditions is incompletely understood. Our previous work has indicated that competitive interaction of either NBS1 or ATMIN with ATM is part of this switch and that overexpression of ATMIN can inhibit NBS1-mediated ATM activation (11). However, the signaling mechanism(s) that favor interaction with one protein over the other in different conditions are unknown.Ubiquitin protein ligase E3 component n-recognin 5 (UBR5) is a very large protein of 2,799 amino acids (309 kDa) belonging to the HECT family of E3 ubiquitin ...

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Dyrk2-associated EDD-DDB1-VprBP E3 Ligase Inhibits Telomerase by TERT Degradation

Cited by 58 publications

References 57 publications

Polo-like Kinase 1 (Plk1) Up-regulates Telomerase Activity by Affecting Human Telomerase Reverse Transcriptase (hTERT) Stability

Polo-like Kinase 1 (Plk1) Up-regulates Telomerase Activity by Affecting Human Telomerase Reverse Transcriptase (hTERT) Stability

Engagement of DYRK2 in proper control for cell division

UBR5-mediated ubiquitination of ATMIN is required for ionizing radiation-induced ATM signaling and function

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