Mathematical modelling of DNA replication reveals a trade-off between coherence of origin activation and robustness against rereplication.

Eukaryotic genomes are duplicated from multiple replication origins exactly once per cell cycle. In Saccharomyces cerevisiae, a complex molecular network has been identified that governs the assembly of the replication machinery. Here we develop a mathematical model that links the dynamics of this n...

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Autores principales:	Anneke Brümmer, Carlos Salazar, Vittoria Zinzalla, Lilia Alberghina, Thomas Höfer
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/1f076e4cfbef4c5c9c6211835bc6feac
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spelling	oai:doaj.org-article:1f076e4cfbef4c5c9c6211835bc6feac2021-12-02T19:58:25ZMathematical modelling of DNA replication reveals a trade-off between coherence of origin activation and robustness against rereplication.1553-734X1553-735810.1371/journal.pcbi.1000783https://doaj.org/article/1f076e4cfbef4c5c9c6211835bc6feac2010-05-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20485558/pdf/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Eukaryotic genomes are duplicated from multiple replication origins exactly once per cell cycle. In Saccharomyces cerevisiae, a complex molecular network has been identified that governs the assembly of the replication machinery. Here we develop a mathematical model that links the dynamics of this network to its performance in terms of rate and coherence of origin activation events, number of activated origins, the resulting distribution of replicon sizes and robustness against DNA rereplication. To parameterize the model, we use measured protein expression data and systematically generate kinetic parameter sets by optimizing the coherence of origin firing. While randomly parameterized networks yield unrealistically slow kinetics of replication initiation, networks with optimized parameters account for the experimentally observed distribution of origin firing times. Efficient inhibition of DNA rereplication emerges as a constraint that limits the rate at which replication can be initiated. In addition to the separation between origin licensing and firing, a time delay between the activation of S phase cyclin-dependent kinase (S-Cdk) and the initiation of DNA replication is required for preventing rereplication. Our analysis suggests that distributive multisite phosphorylation of the S-Cdk targets Sld2 and Sld3 can generate both a robust time delay and contribute to switch-like, coherent activation of replication origins. The proposed catalytic function of the complex formed by Dpb11, Sld3 and Sld2 strongly enhances coherence and robustness of origin firing. The model rationalizes how experimentally observed inefficient replication from fewer origins is caused by premature activation of S-Cdk, while premature activity of the S-Cdk targets Sld2 and Sld3 results in DNA rereplication. Thus the model demonstrates how kinetic deregulation of the molecular network governing DNA replication may result in genomic instability.Anneke BrümmerCarlos SalazarVittoria ZinzallaLilia AlberghinaThomas HöferPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 6, Iss 5, p e1000783 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Anneke Brümmer Carlos Salazar Vittoria Zinzalla Lilia Alberghina Thomas Höfer Mathematical modelling of DNA replication reveals a trade-off between coherence of origin activation and robustness against rereplication.
description	Eukaryotic genomes are duplicated from multiple replication origins exactly once per cell cycle. In Saccharomyces cerevisiae, a complex molecular network has been identified that governs the assembly of the replication machinery. Here we develop a mathematical model that links the dynamics of this network to its performance in terms of rate and coherence of origin activation events, number of activated origins, the resulting distribution of replicon sizes and robustness against DNA rereplication. To parameterize the model, we use measured protein expression data and systematically generate kinetic parameter sets by optimizing the coherence of origin firing. While randomly parameterized networks yield unrealistically slow kinetics of replication initiation, networks with optimized parameters account for the experimentally observed distribution of origin firing times. Efficient inhibition of DNA rereplication emerges as a constraint that limits the rate at which replication can be initiated. In addition to the separation between origin licensing and firing, a time delay between the activation of S phase cyclin-dependent kinase (S-Cdk) and the initiation of DNA replication is required for preventing rereplication. Our analysis suggests that distributive multisite phosphorylation of the S-Cdk targets Sld2 and Sld3 can generate both a robust time delay and contribute to switch-like, coherent activation of replication origins. The proposed catalytic function of the complex formed by Dpb11, Sld3 and Sld2 strongly enhances coherence and robustness of origin firing. The model rationalizes how experimentally observed inefficient replication from fewer origins is caused by premature activation of S-Cdk, while premature activity of the S-Cdk targets Sld2 and Sld3 results in DNA rereplication. Thus the model demonstrates how kinetic deregulation of the molecular network governing DNA replication may result in genomic instability.
format	article
author	Anneke Brümmer Carlos Salazar Vittoria Zinzalla Lilia Alberghina Thomas Höfer
author_facet	Anneke Brümmer Carlos Salazar Vittoria Zinzalla Lilia Alberghina Thomas Höfer
author_sort	Anneke Brümmer
title	Mathematical modelling of DNA replication reveals a trade-off between coherence of origin activation and robustness against rereplication.
title_short	Mathematical modelling of DNA replication reveals a trade-off between coherence of origin activation and robustness against rereplication.
title_full	Mathematical modelling of DNA replication reveals a trade-off between coherence of origin activation and robustness against rereplication.
title_fullStr	Mathematical modelling of DNA replication reveals a trade-off between coherence of origin activation and robustness against rereplication.
title_full_unstemmed	Mathematical modelling of DNA replication reveals a trade-off between coherence of origin activation and robustness against rereplication.
title_sort	mathematical modelling of dna replication reveals a trade-off between coherence of origin activation and robustness against rereplication.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/1f076e4cfbef4c5c9c6211835bc6feac
work_keys_str_mv	AT annekebrummer mathematicalmodellingofdnareplicationrevealsatradeoffbetweencoherenceoforiginactivationandrobustnessagainstrereplication AT carlossalazar mathematicalmodellingofdnareplicationrevealsatradeoffbetweencoherenceoforiginactivationandrobustnessagainstrereplication AT vittoriazinzalla mathematicalmodellingofdnareplicationrevealsatradeoffbetweencoherenceoforiginactivationandrobustnessagainstrereplication AT liliaalberghina mathematicalmodellingofdnareplicationrevealsatradeoffbetweencoherenceoforiginactivationandrobustnessagainstrereplication AT thomashofer mathematicalmodellingofdnareplicationrevealsatradeoffbetweencoherenceoforiginactivationandrobustnessagainstrereplication
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Mathematical modelling of DNA replication reveals a trade-off between coherence of origin activation and robustness against rereplication.

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