Irregular transcription dynamics for rapid production of high-fidelity transcripts

TL;DR

This paper presents a theoretical framework showing how irregular transcription dynamics, including backtracking, enhance transcription fidelity and speed, enabling rapid production of high-fidelity RNA transcripts in physiological conditions.

Contribution

It introduces an analytical model linking backtracking and transcript cleavage to transcription fidelity and speed, revealing how irregular dynamics optimize transcript production.

Findings

Backtracking extends state space, increasing fidelity.

Irregular transcription speeds up high-fidelity transcript production.

Fidelity checkpoints and backtracking together improve accuracy.

Abstract

Both genomic stability and sustenance of day-to-day life rely on efficient and accurate readout of the genetic code. Single-molecule experiments show that transcription and replication are highly stochastic and irregular processes, with the polymerases frequently pausing and even reversing direction. While such behavior is recognized as stemming from a sophisticated proofreading mechanism during replication, the origin and functional significance of irregular transcription dynamics remain controversial. Here, we theoretically examine the implications of RNA polymerase backtracking and transcript cleavage on transcription rates and fidelity. We illustrate how an extended state space for backtracking provides entropic fidelity enhancements that, together with additional fidelity checkpoints, can account for physiological error rates. To explore the competing demands of transcription fidelity, nucleotide triphosphate (NTP) consumption and transcription speed in a physiologically relevant setting, we establish an analytically framework for evaluating transcriptional performance at the level of extended sequences. Using this framework, we reveal a mechanism by which moderately irregular transcription results in astronomical gains in the rate at which extended high-fidelity transcripts can be produced under physiological conditions.