Modelling reveals kinetic advantages of co-transcriptional splicing.
Modelling reveals kinetic advantages of co-transcriptional splicing.
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DOI：
10.1371/journal.pcbi.1002215
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发表时间：
2011-10
影响因子：
4.3
通讯作者：
Beggs JD
中科院分区：
文献类型：
--
作者：
Aitken S;Alexander RD;Beggs JD
信使RNA剪接是去除内含子序列的必要和复杂的过程。尽管剪接机制的组成大多是已知的，但剪接的动力学、剪接因子的催化活性以及转录、剪接和mRNA 3′端形成的相互依赖性还不太清楚。我们提出了一个随机剪接动力学模型，解释了从高分辨率动力学分析的转录，剪接和3′端形成过程中的含内含子的报告基因在芽殖酵母诱导的数据。模型显示，共转录剪接是报告转录本最可能和最有效的剪接途径，部分原因是共转录第二步剪接的正反馈机制。模型比较用于评估反应的替代表示。建模还表明转录和剪接的功能耦合，因为当突变体报告基因中剪接的第二步被废除时，转录起始的速率和剪接的第一步共转录发生的概率都降低了。哺乳动物细胞中蛋白质合成的编码信息首先从DNA转录为信使RNA（mRNA），然后从mRNA翻译为蛋白质。每一步都很复杂，并受到监管。某些DNA序列必须被跳过才能产生功能性蛋白质，这些序列称为内含子，通过剪接过程从mRNA中移除。剪接在所涉及的蛋白质和复合物方面得到了很好的理解，但是反应速率和剪接途径的模型尚未建立。我们提出了一种酵母中剪接的模型，该模型解释了在mRNA被创建的过程中剪接可能发生的可能性，以及一旦mRNA转录完成剪接发生的可能性。我们分配率的反应途径，并表明，共转录剪接是首选的途径。为了得出这些结论，我们比较了一些替代模型的定量计算方法。我们的分析依赖于活细胞中信使RNA的定量测量-这本身就是一个重大挑战，直到最近才得到解决。
Messenger RNA splicing is an essential and complex process for the removal of intron sequences. Whereas the composition of the splicing machinery is mostly known, the kinetics of splicing, the catalytic activity of splicing factors and the interdependency of transcription, splicing and mRNA 3′ end formation are less well understood. We propose a stochastic model of splicing kinetics that explains data obtained from high-resolution kinetic analyses of transcription, splicing and 3′ end formation during induction of an intron-containing reporter gene in budding yeast. Modelling reveals co-transcriptional splicing to be the most probable and most efficient splicing pathway for the reporter transcripts, due in part to a positive feedback mechanism for co-transcriptional second step splicing. Model comparison is used to assess the alternative representations of reactions. Modelling also indicates the functional coupling of transcription and splicing, because both the rate of initiation of transcription and the probability that step one of splicing occurs co-transcriptionally are reduced, when the second step of splicing is abolished in a mutant reporter. The coding information for the synthesis of proteins in mammalian cells is first transcribed from DNA to messenger RNA (mRNA), before being translated from mRNA to protein. Each step is complex, and subject to regulation. Certain sequences of DNA must be skipped in order to generate a functional protein, and these sequences, known as introns, are removed from the mRNA by the process of splicing. Splicing is well understood in terms of the proteins and complexes that are involved, but the rates of reactions, and models for the splicing pathways, have not yet been established. We present a model of splicing in yeast that accounts for the possibilities that splicing may take place while the mRNA is in the process of being created, as well as the possibility that splicing takes place once mRNA transcription is complete. We assign rates to the reactions in the pathway, and show that co-transcriptional splicing is the preferred pathway. In order to reach these conclusions, we compare a number of alternative models by a quantitative computational method. Our analysis relies on the quantitative measurement of messenger RNA in live cells - this is a major challenge in itself that has only recently been addressed.
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活细胞中 RNA 聚合酶 II 的转录周期。
影响因子：
7.8
作者：
Kimura, Hiroshi;Sugaya, Kimihiko;Cook, Peter R
通讯作者：
Cook, Peter R
DOI：
10.1073/pnas.93.11.5208
发表时间：
1996-05-28
影响因子：
11.1
作者：
Iyer, V;Struhl, K
通讯作者：
Struhl, K
影响因子：
16
作者：
Mapendano, Christophe K.;Lykke-Andersen, Soren;Jensen, Torben Heick
通讯作者：
Jensen, Torben Heick
影响因子：
64.5
作者：
Luco RF;Allo M;Schor IE;Kornblihtt AR;Misteli T
通讯作者：
Misteli T
影响因子：
6.8
作者：
AKAIKE, H
通讯作者：
AKAIKE, H