Intermittent Transcription Dynamics for the Rapid Production of Long Transcripts of High Fidelity

Normal cellular function relies on the efficient and accurate readout of the genetic code. Single-molecule experiments show that transcription and replication are highly intermittent processes that are frequently interrupted by polymerases pausing and reversing directions. Although intermittent dynamics in replication are known to result from proofreading, their origin and significance during transcription remain controversial. Here, we theoretically investigate transcriptional fidelity and show that the kinetic scheme provided by the RNA-polymerase backtracking and transcript-cleavage pathway can account for measured error rates. Importantly, we find that intermittent dynamics provide an enormous increase in the rate of producing long transcripts of high fidelity. Our results imply that intermittent dynamics during transcription may have evolved as a way to mitigate the competing demands of speed and fidelity in the transcription of extended sequences. [Display omitted] •Irregular transcription dynamics are a consequence of high-fidelity requirements•A detailed mathematical model of transcriptional proofreading is provided•The tradeoff between transcriptional speed and fidelity is quantitatively explained In this study, Grill and colleagues theoretically investigate RNA-polymerase proofreading through backtracking and show that the energetics of base pairing alone can account for the low transcriptional error rates observed experimentally. Considering transcription performance on genes, they further show that proofreading offers an enormous increase in production rates of high-fidelity transcripts—even though it slows transcription by inducing irregular dynamics. They argue that competition between speed and fidelity is a major selective pressure underlying the intermittent dynamics seen in single-molecule experiments on RNAP.