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酿酒酵母中复制时间的调控。

Regulation of replication timing in Saccharomyces cerevisiae.

作者信息

Berners-Lee Rosie, Gilmore Eamonn, Berkemeier Francisco, Boemo Michael A

机构信息

University of St. Andrews, St. Andrews, Fife, United Kingdom.

Department of Pathology, University of Cambridge, Cambridge, United Kingdom.

出版信息

PLoS Comput Biol. 2025 Jun 2;21(6):e1013066. doi: 10.1371/journal.pcbi.1013066. eCollection 2025 Jun.

DOI:10.1371/journal.pcbi.1013066
PMID:40455924
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12165382/
Abstract

In order to maintain genomic integrity, DNA replication must be highly coordinated. Disruptions in this process can cause replication stress which is aberrant in many pathologies including cancer. Despite this, little is known about the mechanisms governing the temporal regulation of DNA replication initiation, thought to be related to the limited copy number of firing factors. Here, we present a high (1-kilobase) resolution stochastic model of Saccharomyces cerevisiae whole-genome replication in which origins compete to associate with limited firing factors. After developing an algorithm to fit this model to replication timing data, we validated the model by reproducing experimental inter-origin distances, origin efficiencies, and replication fork directionality. This suggests the model accurately simulates the aspects of DNA replication most important for determining its dynamics. We also use the model to predict measures of DNA replication dynamics which are yet to be determined experimentally and investigate the potential impacts of variations in firing factor concentrations on DNA replication.

摘要

为了维持基因组完整性，DNA复制必须高度协调。这一过程的中断会导致复制应激，而复制应激在包括癌症在内的许多病理状况中都是异常的。尽管如此，对于调控DNA复制起始时间的机制我们却知之甚少，一般认为这与起始因子的有限拷贝数有关。在此，我们提出了一个高分辨率（1千碱基）的酿酒酵母全基因组复制随机模型，其中各复制起点竞争与有限的起始因子相结合。在开发出一种将该模型与复制时间数据拟合的算法后，我们通过重现实验测得的复制起点间距离、复制起点效率和复制叉方向性对模型进行了验证。这表明该模型准确地模拟了对确定DNA复制动态最为重要的那些方面。我们还使用该模型来预测尚未通过实验确定的DNA复制动态指标，并研究起始因子浓度变化对DNA复制的潜在影响。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3afe/12165382/5eb47f22692c/pcbi.1013066.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3afe/12165382/0eecd9acd0ca/pcbi.1013066.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3afe/12165382/037fc7386a61/pcbi.1013066.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3afe/12165382/77ad912af3f8/pcbi.1013066.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3afe/12165382/9dc6fbf95bc4/pcbi.1013066.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3afe/12165382/5eb47f22692c/pcbi.1013066.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3afe/12165382/0eecd9acd0ca/pcbi.1013066.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3afe/12165382/037fc7386a61/pcbi.1013066.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3afe/12165382/77ad912af3f8/pcbi.1013066.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3afe/12165382/9dc6fbf95bc4/pcbi.1013066.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3afe/12165382/5eb47f22692c/pcbi.1013066.g005.jpg

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本文引用的文献

1
Neural network and kinetic modelling of human genome replication reveal replication origin locations and strengths.神经网络和人类基因组复制的动力学模型揭示了复制原点的位置和强度。
PLoS Comput Biol. 2023 May 30;19(5):e1011138. doi: 10.1371/journal.pcbi.1011138. eCollection 2023 May.
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Genome-wide measurement of DNA replication fork directionality and quantification of DNA replication initiation and termination with Okazaki fragment sequencing.全基因组水平测量 DNA 复制叉方向，并通过冈崎片段测序定量分析 DNA 复制起始和终止。
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DNA replication timing: Biochemical mechanisms and biological significance.
DNA 复制时间：生化机制与生物学意义。
Bioessays. 2022 Nov;44(11):e2200097. doi: 10.1002/bies.202200097. Epub 2022 Sep 20.
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Nucleosome-directed replication origin licensing independent of a consensus DNA sequence.核小体导向的复制起始点许可与一致 DNA 序列无关。
Nat Commun. 2022 Aug 23;13(1):4947. doi: 10.1038/s41467-022-32657-7.
5
Genome-wide mapping of individual replication fork velocities using nanopore sequencing.利用纳米孔测序进行全基因组范围内个体复制叉速度的绘图。
Nat Commun. 2022 Jun 8;13(1):3295. doi: 10.1038/s41467-022-31012-0.
6
Mapping replication forks, one replicon at a time.逐个复制子定位复制叉。
Mol Cell. 2022 Apr 7;82(7):1246-1248. doi: 10.1016/j.molcel.2022.03.014.
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The Initiation of Eukaryotic DNA Replication.真核生物 DNA 复制的启动。
Annu Rev Biochem. 2022 Jun 21;91:107-131. doi: 10.1146/annurev-biochem-072321-110228. Epub 2022 Mar 23.
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Single-molecule mapping of replisome progression.单分子复制体行进图谱
Mol Cell. 2022 Apr 7;82(7):1372-1382.e4. doi: 10.1016/j.molcel.2022.02.010. Epub 2022 Mar 2.
9
Genome-wide mapping of human DNA replication by optical replication mapping supports a stochastic model of eukaryotic replication.通过光学复制映射对人类 DNA 复制进行全基因组作图，支持真核复制的随机模型。
Mol Cell. 2021 Jul 15;81(14):2975-2988.e6. doi: 10.1016/j.molcel.2021.05.024. Epub 2021 Jun 21.
10
Detection of base analogs incorporated during DNA replication by nanopore sequencing.通过纳米孔测序检测 DNA 复制过程中掺入的碱基类似物。
Nucleic Acids Res. 2020 Sep 4;48(15):e88. doi: 10.1093/nar/gkaa517.