Spiesser T W, Klipp E, Barberis Matteo
Computational Systems Biology, Max Planck Institute for Molecular Genetics, Ihnestrabetae 73, 14195 Berlin, Germany.
Mol Genet Genomics. 2009 Jul;282(1):25-35. doi: 10.1007/s00438-009-0443-9. Epub 2009 Mar 22.
DNA replication in eukaryotes is considered to proceed according to a precise program in which each chromosomal region is duplicated in a defined temporal order. However, recent studies reveal an intrinsic temporal disorder in the replication of yeast chromosome VI. Here we provide a model of the chromosomal duplication to study the temporal sequence of origin activation in budding yeast. The model comprises four parameters that influence the DNA replication system: the lengths of the chromosomes, the explicit chromosomal positions for all replication origins as well as their distinct initiation times and the replication fork migration rate. The designed model is able to reproduce the available experimental data in form of replication profiles. The dynamics of DNA replication was monitored during simulations of wild type and randomly perturbed replication conditions. Severe loss of origin function showed only little influence on the replication dynamics, so systematic deletions of origins (or loss of efficiency) were simulated to provide predictions to be tested experimentally. The simulations provide new insights into the complex system of DNA replication, showing that the system is robust to perturbation, and giving hints about the influence of a possible disordered firing.
真核生物中的DNA复制被认为是按照精确的程序进行的，其中每个染色体区域都按照确定的时间顺序进行复制。然而，最近的研究揭示了酵母染色体VI复制中存在内在的时间无序性。在这里，我们提供了一个染色体复制模型，以研究芽殖酵母中起始点激活的时间顺序。该模型包含四个影响DNA复制系统的参数：染色体长度、所有复制起始点的明确染色体位置及其不同的起始时间，以及复制叉迁移速率。所设计的模型能够以复制图谱的形式重现现有的实验数据。在野生型和随机扰动的复制条件模拟过程中监测了DNA复制的动力学。起始点功能的严重丧失对复制动力学的影响很小，因此模拟了起始点的系统性缺失（或效率丧失），以提供有待实验验证的预测。这些模拟为DNA复制的复杂系统提供了新的见解，表明该系统对扰动具有鲁棒性，并给出了关于可能无序起始的影响的提示。
