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A Dynamic Stochastic Model for DNA Replication Initiation in Early Embryos

Goldar, A; Labit, H; Marheineke, K; Hyrien, O; (2008) A Dynamic Stochastic Model for DNA Replication Initiation in Early Embryos. PLOS ONE , 3 (8) , Article e2919. 10.1371/journal.pone.0002919. Green open access

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Background: Eukaryotic cells seem unable to monitor replication completion during normal S phase, yet must ensure a reliable replication completion time. This is an acute problem in early Xenopus embryos since DNA replication origins are located and activated stochastically, leading to the random completion problem. DNA combing, kinetic modelling and other studies using Xenopus egg extracts have suggested that potential origins are much more abundant than actual initiation events and that the time-dependent rate of initiation, I(t), markedly increases through S phase to ensure the rapid completion of unreplicated gaps and a narrow distribution of completion times. However, the molecular mechanism that underlies this increase has remained obscure.Methodology/Principal Findings: Using both previous and novel DNA combing data we have confirmed that I(t) increases through S phase but have also established that it progressively decreases before the end of S phase. To explore plausible biochemical scenarios that might explain these features, we have performed comparisons between numerical simulations and DNA combing data. Several simple models were tested: i) recycling of a limiting replication fork component from completed replicons; ii) time-dependent increase in origin efficiency; iii) time-dependent increase in availability of an initially limiting factor, e. g. by nuclear import. None of these potential mechanisms could on its own account for the data. We propose a model that combines time-dependent changes in availability of a replication factor and a fork-density dependent affinity of this factor for potential origins. This novel model quantitatively and robustly accounted for the observed changes in initiation rate and fork density.Conclusions/Significance: This work provides a refined temporal profile of replication initiation rates and a robust, dynamic model that quantitatively explains replication origin usage during early embryonic S phase. These results have significant implications for the organisation of replication origins in higher eukaryotes.

Type: Article
Title: A Dynamic Stochastic Model for DNA Replication Initiation in Early Embryos
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0002919
Publisher version: http://dx.doi.org/10.1371/journal.pone.0002919
Language: English
Additional information: © 2008 Goldar et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The O.H. lab is supported by the Association pour la Recherche sur le Cancer, the Ligue Contre le Cancer (Comité de Paris), the Agence Nationale pour la Recherche and the Fondation pour la Recherche Médicale. H.L. was supported by fellowships from the MENESR and the ARC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/111935
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