  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.
