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Cyclin-dependent kinase regulates the length of S phase through TICRR/TRESLIN phosphorylation
S-phase cyclin-dependent kinases (CDKs) stimulate replication initiation and accelerate progression through the replication timing program, but it is unknown which CDK substrates are responsible for these effects. CDK phosphorylation of the replication factor TICRR (TopBP1-interacting checkpoint and...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358407/ https://www.ncbi.nlm.nih.gov/pubmed/25737283 http://dx.doi.org/10.1101/gad.246827.114 |
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author | Sansam, Courtney G. Goins, Duane Siefert, Joseph C. Clowdus, Emily A. Sansam, Christopher L. |
author_facet | Sansam, Courtney G. Goins, Duane Siefert, Joseph C. Clowdus, Emily A. Sansam, Christopher L. |
author_sort | Sansam, Courtney G. |
collection | PubMed |
description | S-phase cyclin-dependent kinases (CDKs) stimulate replication initiation and accelerate progression through the replication timing program, but it is unknown which CDK substrates are responsible for these effects. CDK phosphorylation of the replication factor TICRR (TopBP1-interacting checkpoint and replication regulator)/TRESLIN is required for DNA replication. We show here that phosphorylated TICRR is limiting for S-phase progression. Overexpression of a TICRR mutant with phosphomimetic mutations at two key CDK-phosphorylated residues (TICRR(TESE)) stimulates DNA synthesis and shortens S phase by increasing replication initiation. This effect requires the TICRR region that is necessary for its interaction with MDM two-binding protein. Expression of TICRR(TESE) does not grossly alter the spatial organization of replication forks in the nucleus but does increase replication clusters and the number of replication forks within each cluster. In contrast to CDK hyperactivation, the acceleration of S-phase progression by TICRR(TESE) does not induce DNA damage. These results show that CDK can stimulate initiation and compress the replication timing program by phosphorylating a single protein, suggesting a simple mechanism by which S-phase length is controlled. |
format | Online Article Text |
id | pubmed-4358407 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-43584072015-09-01 Cyclin-dependent kinase regulates the length of S phase through TICRR/TRESLIN phosphorylation Sansam, Courtney G. Goins, Duane Siefert, Joseph C. Clowdus, Emily A. Sansam, Christopher L. Genes Dev Research Paper S-phase cyclin-dependent kinases (CDKs) stimulate replication initiation and accelerate progression through the replication timing program, but it is unknown which CDK substrates are responsible for these effects. CDK phosphorylation of the replication factor TICRR (TopBP1-interacting checkpoint and replication regulator)/TRESLIN is required for DNA replication. We show here that phosphorylated TICRR is limiting for S-phase progression. Overexpression of a TICRR mutant with phosphomimetic mutations at two key CDK-phosphorylated residues (TICRR(TESE)) stimulates DNA synthesis and shortens S phase by increasing replication initiation. This effect requires the TICRR region that is necessary for its interaction with MDM two-binding protein. Expression of TICRR(TESE) does not grossly alter the spatial organization of replication forks in the nucleus but does increase replication clusters and the number of replication forks within each cluster. In contrast to CDK hyperactivation, the acceleration of S-phase progression by TICRR(TESE) does not induce DNA damage. These results show that CDK can stimulate initiation and compress the replication timing program by phosphorylating a single protein, suggesting a simple mechanism by which S-phase length is controlled. Cold Spring Harbor Laboratory Press 2015-03-01 /pmc/articles/PMC4358407/ /pubmed/25737283 http://dx.doi.org/10.1101/gad.246827.114 Text en © 2015 Sansam et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/. |
spellingShingle | Research Paper Sansam, Courtney G. Goins, Duane Siefert, Joseph C. Clowdus, Emily A. Sansam, Christopher L. Cyclin-dependent kinase regulates the length of S phase through TICRR/TRESLIN phosphorylation |
title | Cyclin-dependent kinase regulates the length of S phase through TICRR/TRESLIN phosphorylation |
title_full | Cyclin-dependent kinase regulates the length of S phase through TICRR/TRESLIN phosphorylation |
title_fullStr | Cyclin-dependent kinase regulates the length of S phase through TICRR/TRESLIN phosphorylation |
title_full_unstemmed | Cyclin-dependent kinase regulates the length of S phase through TICRR/TRESLIN phosphorylation |
title_short | Cyclin-dependent kinase regulates the length of S phase through TICRR/TRESLIN phosphorylation |
title_sort | cyclin-dependent kinase regulates the length of s phase through ticrr/treslin phosphorylation |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358407/ https://www.ncbi.nlm.nih.gov/pubmed/25737283 http://dx.doi.org/10.1101/gad.246827.114 |
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