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Uncovering the role of APC-Cdh1 in generating the dynamics of S-phase onset

Cdh1, a coactivator of the anaphase-promoting complex (APC), is a potential tumor suppressor. Cdh1 ablation promotes precocious S-phase entry, but it was unclear how this affects DNA replication dynamics while contributing to genomic instability and tumorigenesis. We find that Cdh1 depletion causes...

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Autores principales: Yuan, Xi, Srividhya, Jeyaraman, De Luca, Thomas, Lee, Ju-hyong E., Pomerening, Joseph R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3923637/
https://www.ncbi.nlm.nih.gov/pubmed/24356446
http://dx.doi.org/10.1091/mbc.E13-08-0480
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author Yuan, Xi
Srividhya, Jeyaraman
De Luca, Thomas
Lee, Ju-hyong E.
Pomerening, Joseph R.
author_facet Yuan, Xi
Srividhya, Jeyaraman
De Luca, Thomas
Lee, Ju-hyong E.
Pomerening, Joseph R.
author_sort Yuan, Xi
collection PubMed
description Cdh1, a coactivator of the anaphase-promoting complex (APC), is a potential tumor suppressor. Cdh1 ablation promotes precocious S-phase entry, but it was unclear how this affects DNA replication dynamics while contributing to genomic instability and tumorigenesis. We find that Cdh1 depletion causes early S-phase onset in conjunction with increase in Rb/E2F1-mediated cyclin E1 expression, but reduced levels of cyclin E1 protein promote this transition. We hypothesize that this is due to a weakened cyclin-dependent kinase inhibitor (CKI)–cyclin-dependent kinase 2 positive-feedback loop, normally generated by APC-Cdh1–mediated proteolysis of Skp2. Indeed, Cdh1 depletion increases Skp2 abundance while diminishing levels of the CKI p27. This lowers the level of cyclin E1 needed for S-phase entry and delays cyclin E1 proteolysis during S-phase progression while corresponding to slowed replication fork movement and reduced frequency of termination events. In summary, using both experimental and computational approaches, we show that APC-Cdh1 establishes a stimulus–response relationship that promotes S phase by ensuring that proper levels of p27 accumulate during G1 phase, and defects in its activation accelerate the timing of S-phase onset while prolonging its progression.
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spelling pubmed-39236372014-04-30 Uncovering the role of APC-Cdh1 in generating the dynamics of S-phase onset Yuan, Xi Srividhya, Jeyaraman De Luca, Thomas Lee, Ju-hyong E. Pomerening, Joseph R. Mol Biol Cell Articles Cdh1, a coactivator of the anaphase-promoting complex (APC), is a potential tumor suppressor. Cdh1 ablation promotes precocious S-phase entry, but it was unclear how this affects DNA replication dynamics while contributing to genomic instability and tumorigenesis. We find that Cdh1 depletion causes early S-phase onset in conjunction with increase in Rb/E2F1-mediated cyclin E1 expression, but reduced levels of cyclin E1 protein promote this transition. We hypothesize that this is due to a weakened cyclin-dependent kinase inhibitor (CKI)–cyclin-dependent kinase 2 positive-feedback loop, normally generated by APC-Cdh1–mediated proteolysis of Skp2. Indeed, Cdh1 depletion increases Skp2 abundance while diminishing levels of the CKI p27. This lowers the level of cyclin E1 needed for S-phase entry and delays cyclin E1 proteolysis during S-phase progression while corresponding to slowed replication fork movement and reduced frequency of termination events. In summary, using both experimental and computational approaches, we show that APC-Cdh1 establishes a stimulus–response relationship that promotes S phase by ensuring that proper levels of p27 accumulate during G1 phase, and defects in its activation accelerate the timing of S-phase onset while prolonging its progression. The American Society for Cell Biology 2014-02-15 /pmc/articles/PMC3923637/ /pubmed/24356446 http://dx.doi.org/10.1091/mbc.E13-08-0480 Text en © 2014 Yuan et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology.
spellingShingle Articles
Yuan, Xi
Srividhya, Jeyaraman
De Luca, Thomas
Lee, Ju-hyong E.
Pomerening, Joseph R.
Uncovering the role of APC-Cdh1 in generating the dynamics of S-phase onset
title Uncovering the role of APC-Cdh1 in generating the dynamics of S-phase onset
title_full Uncovering the role of APC-Cdh1 in generating the dynamics of S-phase onset
title_fullStr Uncovering the role of APC-Cdh1 in generating the dynamics of S-phase onset
title_full_unstemmed Uncovering the role of APC-Cdh1 in generating the dynamics of S-phase onset
title_short Uncovering the role of APC-Cdh1 in generating the dynamics of S-phase onset
title_sort uncovering the role of apc-cdh1 in generating the dynamics of s-phase onset
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3923637/
https://www.ncbi.nlm.nih.gov/pubmed/24356446
http://dx.doi.org/10.1091/mbc.E13-08-0480
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