Development of a "Modular" Scheme to Describe the Kinetics of Transcript Elongation by RNA Polymerase

Transcript elongation by RNA polymerase involves the sequential appearance of several alternative and off-pathway states of the transcript elongation complex (TEC), and this complicates modeling of the kinetics of the transcription elongation process. Based on solutions of the chemical master equation for such transcription systems as a function of time, we here develop a modular scheme for simulating such kinetic transcription data. This scheme deals explicitly with the problem of TEC desynchronization as transcript synthesis proceeds, and develops kinetic modules to permit the various alternative states of the TECs (paused states, backtracked states, arrested states, and terminated states) to be introduced one-by-one as needed. In this way, we can set up a comprehensive kinetic model of appropriate complexity to fit the known transcriptional properties of any given DNA template and set of experimental conditions, including regulatory cofactors. In the companion article, this modular scheme is successfully used to model kinetic transcription elongation data obtained by bulk-gel electrophoresis quenching procedures and real-time surface plasmon resonance methods from a template of known sequence that contains defined pause, stall, and termination sites.