A Dynamic Stochastic Model for DNA Replication Initiation in Early Embryos
A Dynamic Stochastic Model for DNA Replication Initiation in Early Embryos
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DOI：
10.1371/journal.pone.0002919
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发表时间：
2008-08-06
期刊：
影响因子：
3.7
通讯作者：
Hyrien, Olivier
中科院分区：
文献类型：
--
作者：
Goldar, Arach;Labit, Helene;Hyrien, Olivier
背景资料：真核细胞似乎无法监测复制完成在正常的S期，但必须确保一个可靠的复制完成时间。这在早期非洲爪蟾胚胎中是一个严重的问题，因为DNA复制起点的定位和激活是随机的，导致随机完成问题。DNA梳理、动力学建模和其他使用爪蟾卵提取物的研究表明，潜在的起源比实际的起始事件丰富得多，并且起始的时间依赖性速率I（t）通过S期显著增加，以确保未复制的间隙的快速完成和完成时间的窄分布。然而，这种增加的分子机制，这一基础仍然是obvious.Methodology/主要调查结果：使用以前的和新的DNA梳理数据，我们已经证实，I（t）增加通过S期，但也建立了S期结束前，它逐渐减少。为了探索可能解释这些特征的合理的生化情景，我们在数值模拟和DNA梳理数据之间进行了比较。测试了几个简单的模型：i）从完成的复制子中回收限制性复制叉组分; ii）起始效率的时间依赖性增加; iii）初始限制因子的可用性的时间依赖性增加，e. G.核进口。这些潜在的机制都不能单独解释这些数据。我们提出了一个模型，结合了时间依赖性的变化，在可用性的复制因子和叉密度依赖的亲和力，这个因素的潜在的起源。这种新的模型定量和鲁棒占所观察到的变化，在启动率和叉density.Conclusions/意义：这项工作提供了一个完善的时间分布的复制启动率和一个强大的，动态的模型，定量解释复制起点的使用在早期胚胎S期。这些结果有显着的影响，在高等真核生物复制起点的组织。
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.