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Kinetic proofreading is a class of error-correcting mechanisms in biology that expend energy to avoid mistakes during replication, transcription, and translation. Proofreading is typically assumed to evolve when selection for fidelity outweighs costs in energy and the speed of replication. We show that when stalling after misincorporations is accounted for, proofreading can instead speed up replication. Consistent with data on polymerase mutagenesis, our results suggest that proofreading can evolve under selection for speed alone. We generalize to multicomponent self-assembly and show that analogous error-correcting processes, such as dynamic instability, can likewise emerge purely from selection for rapid assembly. Thus, nonequilibrium error correction can evolve from selection for speed, even without direct fidelity advantages. We discuss implications for mutation-rate evolution, molecular assembly processes, and models of early life.
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This content will become publicly available on March 5, 2027
Collective RNAP Dynamics Link Transcriptional Strength to Fidelity
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.
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- Award ID(s):
- 2019745
- PAR ID:
- 10687496
- Publisher / Repository:
- American Chemical Society
- Date Published:
- Journal Name:
- The Journal of Physical Chemistry Letters
- Volume:
- 17
- Issue:
- 9
- ISSN:
- 1948-7185
- Page Range / eLocation ID:
- 2666 to 2672
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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