Cargando…
Cdc6 is sequentially regulated by PP2A-Cdc55, Cdc14, and Sic1 for origin licensing in S. cerevisiae
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 phosphorylati...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8830886/ https://www.ncbi.nlm.nih.gov/pubmed/35142288 http://dx.doi.org/10.7554/eLife.74437 |
_version_ | 1784648378491076608 |
---|---|
author | Philip, Jasmin Örd, Mihkel Silva, Andriele Singh, Shaneen Diffley, John FX Remus, Dirk Loog, Mart Ikui, Amy E |
author_facet | Philip, Jasmin Örd, Mihkel Silva, Andriele Singh, Shaneen Diffley, John FX Remus, Dirk Loog, Mart Ikui, Amy E |
author_sort | Philip, Jasmin |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8830886 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-88308862022-02-14 Cdc6 is sequentially regulated by PP2A-Cdc55, Cdc14, and Sic1 for origin licensing in S. cerevisiae Philip, Jasmin Örd, Mihkel Silva, Andriele Singh, Shaneen Diffley, John FX Remus, Dirk Loog, Mart Ikui, Amy E eLife Cell Biology 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. eLife Sciences Publications, Ltd 2022-02-10 /pmc/articles/PMC8830886/ /pubmed/35142288 http://dx.doi.org/10.7554/eLife.74437 Text en © 2022, Philip et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cell Biology Philip, Jasmin Örd, Mihkel Silva, Andriele Singh, Shaneen Diffley, John FX Remus, Dirk Loog, Mart Ikui, Amy E Cdc6 is sequentially regulated by PP2A-Cdc55, Cdc14, and Sic1 for origin licensing in S. cerevisiae |
title | Cdc6 is sequentially regulated by PP2A-Cdc55, Cdc14, and Sic1 for origin licensing in S. cerevisiae |
title_full | Cdc6 is sequentially regulated by PP2A-Cdc55, Cdc14, and Sic1 for origin licensing in S. cerevisiae |
title_fullStr | Cdc6 is sequentially regulated by PP2A-Cdc55, Cdc14, and Sic1 for origin licensing in S. cerevisiae |
title_full_unstemmed | Cdc6 is sequentially regulated by PP2A-Cdc55, Cdc14, and Sic1 for origin licensing in S. cerevisiae |
title_short | Cdc6 is sequentially regulated by PP2A-Cdc55, Cdc14, and Sic1 for origin licensing in S. cerevisiae |
title_sort | cdc6 is sequentially regulated by pp2a-cdc55, cdc14, and sic1 for origin licensing in s. cerevisiae |
topic | Cell Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8830886/ https://www.ncbi.nlm.nih.gov/pubmed/35142288 http://dx.doi.org/10.7554/eLife.74437 |
work_keys_str_mv | AT philipjasmin cdc6issequentiallyregulatedbypp2acdc55cdc14andsic1fororiginlicensinginscerevisiae AT ordmihkel cdc6issequentiallyregulatedbypp2acdc55cdc14andsic1fororiginlicensinginscerevisiae AT silvaandriele cdc6issequentiallyregulatedbypp2acdc55cdc14andsic1fororiginlicensinginscerevisiae AT singhshaneen cdc6issequentiallyregulatedbypp2acdc55cdc14andsic1fororiginlicensinginscerevisiae AT diffleyjohnfx cdc6issequentiallyregulatedbypp2acdc55cdc14andsic1fororiginlicensinginscerevisiae AT remusdirk cdc6issequentiallyregulatedbypp2acdc55cdc14andsic1fororiginlicensinginscerevisiae AT loogmart cdc6issequentiallyregulatedbypp2acdc55cdc14andsic1fororiginlicensinginscerevisiae AT ikuiamye cdc6issequentiallyregulatedbypp2acdc55cdc14andsic1fororiginlicensinginscerevisiae |