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A quantitative model of the initiation of DNA replication in Saccharomyces cerevisiae predicts the effects of system perturbations
BACKGROUND: Eukaryotic cell proliferation involves DNA replication, a tightly regulated process mediated by a multitude of protein factors. In budding yeast, the initiation of replication is facilitated by the heterohexameric origin recognition complex (ORC). ORC binds to specific origins of replica...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3439281/ https://www.ncbi.nlm.nih.gov/pubmed/22738223 http://dx.doi.org/10.1186/1752-0509-6-78 |
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author | Gidvani, Rohan D Sudmant, Peter Li, Grace DaSilva, Lance F McConkey, Brendan J Duncker, Bernard P Ingalls, Brian P |
author_facet | Gidvani, Rohan D Sudmant, Peter Li, Grace DaSilva, Lance F McConkey, Brendan J Duncker, Bernard P Ingalls, Brian P |
author_sort | Gidvani, Rohan D |
collection | PubMed |
description | BACKGROUND: Eukaryotic cell proliferation involves DNA replication, a tightly regulated process mediated by a multitude of protein factors. In budding yeast, the initiation of replication is facilitated by the heterohexameric origin recognition complex (ORC). ORC binds to specific origins of replication and then serves as a scaffold for the recruitment of other factors such as Cdt1, Cdc6, the Mcm2-7 complex, Cdc45 and the Dbf4-Cdc7 kinase complex. While many of the mechanisms controlling these associations are well documented, mathematical models are needed to explore the network’s dynamic behaviour. We have developed an ordinary differential equation-based model of the protein-protein interaction network describing replication initiation. RESULTS: The model was validated against quantified levels of protein factors over a range of cell cycle timepoints. Using chromatin extracts from synchronized Saccharomyces cerevisiae cell cultures, we were able to monitor the in vivo fluctuations of several of the aforementioned proteins, with additional data obtained from the literature. The model behaviour conforms to perturbation trials previously reported in the literature, and accurately predicts the results of our own knockdown experiments. Furthermore, we successfully incorporated our replication initiation model into an established model of the entire yeast cell cycle, thus providing a comprehensive description of these processes. CONCLUSIONS: This study establishes a robust model of the processes driving DNA replication initiation. The model was validated against observed cell concentrations of the driving factors, and characterizes the interactions between factors implicated in eukaryotic DNA replication. Finally, this model can serve as a guide in efforts to generate a comprehensive model of the mammalian cell cycle in order to explore cancer-related phenotypes. |
format | Online Article Text |
id | pubmed-3439281 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-34392812012-09-17 A quantitative model of the initiation of DNA replication in Saccharomyces cerevisiae predicts the effects of system perturbations Gidvani, Rohan D Sudmant, Peter Li, Grace DaSilva, Lance F McConkey, Brendan J Duncker, Bernard P Ingalls, Brian P BMC Syst Biol Research Article BACKGROUND: Eukaryotic cell proliferation involves DNA replication, a tightly regulated process mediated by a multitude of protein factors. In budding yeast, the initiation of replication is facilitated by the heterohexameric origin recognition complex (ORC). ORC binds to specific origins of replication and then serves as a scaffold for the recruitment of other factors such as Cdt1, Cdc6, the Mcm2-7 complex, Cdc45 and the Dbf4-Cdc7 kinase complex. While many of the mechanisms controlling these associations are well documented, mathematical models are needed to explore the network’s dynamic behaviour. We have developed an ordinary differential equation-based model of the protein-protein interaction network describing replication initiation. RESULTS: The model was validated against quantified levels of protein factors over a range of cell cycle timepoints. Using chromatin extracts from synchronized Saccharomyces cerevisiae cell cultures, we were able to monitor the in vivo fluctuations of several of the aforementioned proteins, with additional data obtained from the literature. The model behaviour conforms to perturbation trials previously reported in the literature, and accurately predicts the results of our own knockdown experiments. Furthermore, we successfully incorporated our replication initiation model into an established model of the entire yeast cell cycle, thus providing a comprehensive description of these processes. CONCLUSIONS: This study establishes a robust model of the processes driving DNA replication initiation. The model was validated against observed cell concentrations of the driving factors, and characterizes the interactions between factors implicated in eukaryotic DNA replication. Finally, this model can serve as a guide in efforts to generate a comprehensive model of the mammalian cell cycle in order to explore cancer-related phenotypes. BioMed Central 2012-06-27 /pmc/articles/PMC3439281/ /pubmed/22738223 http://dx.doi.org/10.1186/1752-0509-6-78 Text en Copyright ©2012 Gidvani et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Gidvani, Rohan D Sudmant, Peter Li, Grace DaSilva, Lance F McConkey, Brendan J Duncker, Bernard P Ingalls, Brian P A quantitative model of the initiation of DNA replication in Saccharomyces cerevisiae predicts the effects of system perturbations |
title | A quantitative model of the initiation of DNA replication in Saccharomyces cerevisiae predicts the effects of system perturbations |
title_full | A quantitative model of the initiation of DNA replication in Saccharomyces cerevisiae predicts the effects of system perturbations |
title_fullStr | A quantitative model of the initiation of DNA replication in Saccharomyces cerevisiae predicts the effects of system perturbations |
title_full_unstemmed | A quantitative model of the initiation of DNA replication in Saccharomyces cerevisiae predicts the effects of system perturbations |
title_short | A quantitative model of the initiation of DNA replication in Saccharomyces cerevisiae predicts the effects of system perturbations |
title_sort | quantitative model of the initiation of dna replication in saccharomyces cerevisiae predicts the effects of system perturbations |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3439281/ https://www.ncbi.nlm.nih.gov/pubmed/22738223 http://dx.doi.org/10.1186/1752-0509-6-78 |
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