MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh EH4 2XU, UK.
J R Soc Interface. 2013 Jun 26;10(86):20130438. doi: 10.1098/rsif.2013.0438. Print 2013 Sep 6.
The complexity of many RNA processing pathways is such that a conventional systems modelling approach is inadequate to represent all the molecular species involved. We demonstrate that rule-based modelling permits a detailed model of a complex RNA signalling pathway to be defined. Phosphorylation of the RNA polymerase II (RNAPII) C-terminal domain (CTD; a flexible tail-like extension of the largest subunit) couples pre-messenger RNA capping, splicing and 3' end maturation to transcriptional elongation and termination, and plays a central role in integrating these processes. The phosphorylation states of the serine residues of many heptapeptide repeats of the CTD alter along the coding region of genes as a function of distance from the promoter. From a mechanistic perspective, both the changes in phosphorylation and the location at which they take place on the genes are a function of the time spent by RNAPII in elongation as this interval provides the opportunity for the kinases and phosphatases to interact with the CTD. On this basis, we synthesize the available data to create a kinetic model of the action of the known kinases and phosphatases to resolve the phosphorylation pathways and their kinetics.
许多 RNA 加工途径的复杂性使得传统的系统建模方法不足以表示涉及的所有分子种类。我们证明，基于规则的建模允许定义复杂的 RNA 信号通路的详细模型。RNA 聚合酶 II (RNAPII) C 末端结构域（CTD；最大亚基的灵活尾巴状延伸）的磷酸化将前信使 RNA 加帽、剪接和 3' 端成熟与转录延伸和终止偶联，并且在整合这些过程中发挥核心作用。CTD 的许多七肽重复的丝氨酸残基的磷酸化状态随着基因编码区的距离从启动子的变化而变化。从机械的角度来看，磷酸化的变化及其发生的位置都是 RNAPII 在延伸过程中花费的时间的函数，因为这个间隔为激酶和磷酸酶与 CTD 相互作用提供了机会。在此基础上，我们综合了可用的数据来创建一个已知激酶和磷酸酶作用的动力学模型，以解决磷酸化途径及其动力学。
