Transcription fidelity is inherently coupled to its strength, and highly expressed genes often exhibit elevated error rates. Epigenetic and structural factors, including histone modifications, DNA methylation, and nucleoid-associated proteins, modulate transcriptional output and, consequently, fidelity. However, the mechanistic origin of this fidelity-strength relationship remains poorly understood. Here, we propose that repulsive interactions among cotranscribing RNA polymerases (RNAPs) might explain these couplings. We develop a stochastic kinetic model of transcription elongation that incorporates both kinetic proofreading and repulsive forces generated through collisions between the neighboring RNAPs. In this framework, it is found that the collision forces accelerate leading RNAPs' elongation speed and impede their kinetic proofreading; the opposite trends occur for the trailing enzymes. As a result, interactions among multiple RNAPs at high initiation rates substantially elevate transcriptional error relative to isolated enzymes, with the magnitude of this increase determined by the intrinsic proofreading rate. In contrast, the mechanical partitioning of force between forward translocation and backtracking pathways primarily modulates elongation speed without altering fidelity. Together, our study provides a quantitative and mechanistic framework that links the collective dynamics of RNAPs to transcriptional errors, offering new physical insights into how transcriptional strength intrinsically compromises fidelity.
Midha et al. (Thu,) studied this question.