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OTUD6A activates CDC6. 7 / 7
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"Taken together, these data demonstrated that OTUD6A maintains CDC6 stability, removes K6-, K33- and K48-linked polyubiquitin chains, and reverses CDC6 degradation caused by APC/C-CDH1 and SCF-Cyclin F. OTUD6A participates in cell cycle progression by regulating CDC6."
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"Moreover, OTUD6A promotes cell proliferation and decreases sensitivity to chemotherapy by upregulating CDC6."
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"The upregulation of CDC6 by OTUD6A was not due to changes in the cell cycle as neither stable overexpression nor knockdown of OTUD6A influenced the cell cycle distribution in asynchronous cells (Supplementary Fig. 1k, l)."
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"Moreover, knockdown of OTUD6A was accompanied by decreased loading of MCM2, a subunit of pre-RC, onto chromatin (Fig. 1h), suggesting that knockdown of OTUD6A prevents pre-RC assembly.To confirm the role of OTUD6A in CDC6 regulation in vivo, we crossed Otud6a mice with Dppa3-Cre (which exert efficient Cre recombination enzyme activity during the early stage of embryonic development and in germ cell line [30]) mice to generate conditional Otud6a knockout (CKO) mice (Supplementary Fig. 1o, p)."
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"The half-life of the endogenous CDC6 protein was prolonged in OTUD6A-overexpressing cells (Fig. 3a), whereas knockdown or knockout of OTUD6A led to a shortened half-life (Fig. 3b, c and Supplementary Fig. 3a), suggesting that OTUD6A inhibits CDC6 degradation."
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"Overexpression of OTUD6A upregulated CDC6 protein level and prolonged the half-life of the CDC6 protein, independent of its phosphorylation status (Supplementary Fig. 3c-e)."
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"Ubiquitin-proteasome system and the autophagy-lysosome pathway are the two main mechanisms responsible for intracellular protein degradation [34], we next clarified the pathway involved in OTUD6A-mediated CDC6 regulation."
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