Cdc6 is sequentially regulated by PP2A-Cdc55, Cdc14, and Sic1 for origin licensing in S. cerevisiae .
| Autor: | Philip J; The PhD Program in Biochemistry, The Graduate Center, CUNY, Brooklyn, United States.; Brooklyn College, Brooklyn, United States., Örd M; University of Tartu, Tartu, Estonia., Silva A; The PhD Program in Biochemistry, The Graduate Center, CUNY, Brooklyn, United States.; Brooklyn College, Brooklyn, United States., Singh S; The PhD Program in Biochemistry, The Graduate Center, CUNY, Brooklyn, United States.; Brooklyn College, Brooklyn, United States., Diffley JF; The Francis Crick Institute, London, United Kingdom., Remus D; Memorial Sloan-Kettering Cancer Center, New York, United States., Loog M; University of Tartu, Tartu, Estonia., Ikui AE; The PhD Program in Biochemistry, The Graduate Center, CUNY, Brooklyn, United States.; Brooklyn College, Brooklyn, United States. |
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| Jazyk: | angličtina |
| Zdroj: | ELife [Elife] 2022 Feb 10; Vol. 11. Date of Electronic Publication: 2022 Feb 10. |
| DOI: | 10.7554/eLife.74437 |
| Abstrakt: | Cdc6, a subunit of the pre-replicative complex (pre-RC), contains multiple regulatory cyclin-dependent kinase (Cdk1) consensus sites, SP or TP motifs. In Saccharomyces cerevisiae , Cdk1 phosphorylates Cdc6-T7 to recruit Cks1, the Cdk1 phospho-adaptor in S phase, for subsequent multisite phosphorylation and protein degradation. Cdc6 accumulates in mitosis and is tightly bound by Clb2 through N-terminal phosphorylation in order to prevent premature origin licensing and degradation. It has been extensively studied how Cdc6 phosphorylation is regulated by the cyclin-Cdk1 complex. However, a detailed mechanism on how Cdc6 phosphorylation is reversed by phosphatases has not been elucidated. Here, we show that PP2A Cdc55 dephosphorylates Cdc6 N-terminal sites to release Clb2. Cdc14 dephosphorylates the C-terminal phospho-degron, leading to Cdc6 stabilization in mitosis. In addition, Cdk1 inhibitor Sic1 releases Clb2·Cdk1·Cks1 from Cdc6 to load Mcm2-7 on the chromatin upon mitotic exit. Thus, pre-RC assembly and origin licensing are promoted by phosphatases through the attenuation of distinct Cdk1-dependent Cdc6 inhibitory mechanisms. Competing Interests: JP, MÖ, AS, SS, JD, DR, ML, AI No competing interests declared (© 2022, Philip et al.) |
| Databáze: | MEDLINE |
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