Cdc6 is sequentially regulated by PP2A-Cdc55, Cdc14, and Sic1 for origin licensing in S. cerevisiae Journal Article
| Authors: | Philip, J.; Örd, M.; Silva, A.; Singh, S.; Diffley, J. FX.; Remus, D.; Loog, M.; Ikui, A. E. |
| Article Title: | Cdc6 is sequentially regulated by PP2A-Cdc55, Cdc14, and Sic1 for origin licensing in S. cerevisiae |
| Abstract: | 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 PP2ACdc55 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. © 2022, Philip et al. |
| Keywords: | dna replication; mitosis; cell cycle protein; metabolism; cell cycle proteins; phosphatase; phosphorylation; physiology; saccharomyces cerevisiae; protein tyrosine phosphatase; saccharomyces cerevisiae proteins; saccharomyces cerevisiae protein; cyclin dependent kinase inhibitor; cell biology; protein phosphatase 2; pp2a; protein tyrosine phosphatases; phosphoprotein phosphatase 2; s. cerevisiae; cdc14; cyclin-dependent kinase inhibitor proteins; cdc6; cdc55; cdc14 protein, s cerevisiae; cdc55 protein, s cerevisiae; cdc6 protein, s cerevisiae; sic1 protein, s cerevisiae |
| Journal Title: | eLife |
| Volume: | 11 |
| ISSN: | 2050-084X |
| Publisher: | eLife Sciences Publications Ltd. |
| Date Published: | 2022-02-10 |
| Start Page: | e74437 |
| Language: | English |
| DOI: | 10.7554/eLife.74437 |
| PUBMED: | 35142288 |
| PROVIDER: | scopus |
| PMCID: | PMC8830886 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 April 2022 -- Source: Scopus |
