Journal
ELIFE
Volume 11, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.74437
Keywords
Cdc6; PP2A; Cdc55; DNA replication; phosphatase; Cdc14; S; cerevisiae
Categories
Funding
- PSC-CUNY Enhanced Award [64657-00 52]
- National Institute of General Medical Sciences [R01-GM127428, R01-GM107239]
- National Institutes of Health [P30 CA008748]
- Centre of Excellence for 'Molecular Cell Technologies' [TK143]
- Estonian Research Council [PRG550]
- Francis Crick Institute [FC001066]
- European Research Council [649124]
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This study reveals that PP2A(Cdc55) dephosphorylates the N-terminal sites of Cdc6 to release Clb2, while Cdc14 dephosphorylates the C-terminal phospho-degron to stabilize Cdc6 in mitosis. Additionally, the Cdk1 inhibitor Sic1 releases Clb2·Cdk1·Cks1 from Cdc6 to load Mcm2-7 on the chromatin upon mitotic exit. The findings suggest that phosphatases promote pre-RC assembly and origin licensing through the attenuation of different Cdk1-dependent inhibitory mechanisms of Cdc6.
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 center dot Cdk1 center dot 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.
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