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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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This content will become publicly available on April 17, 2027
Adaptive Mechanical Proofreading Toward Robust yet Tunable Humoral Immunity
To reliably transmit information, cells exploit nonequilibrium drives to reduce errors. Kinetic proofreading is a classic mechanism that sharpens ligand discrimination by T lymphocytes, yet it remains unclear whether adaptive immunity relies on kinetic proofreading alone to achieve high fidelity. Here, we propose an alternative: an enhanced form of mechanical proofreading (MPR), in which adaptive force generation during dynamic cell-cell contact enables faithful selection of high-affinity B lymphocytes. Using a coarse-grained model validated by experiments, we show that adaptive MPR, characterized by mechanical feedback between force exertion and contact formation, supports robust discrimination of receptor quality regardless of ligand quantity. While MPR generally balances tradeoffs between speed and fidelity, a negative scaling of contact duration with ligand abundance reveals the presence of feedback. By modulating interactions among distinct ligands that share mechanical load at membrane contacts, adaptive MPR may help mitigate autoimmunity or enhance multivalent vaccines. Overall, this work generalizes proofreading to include cellular designs that operate across scales to reconcile competing functional demands at the systems level.
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- PAR ID:
- 10704767
- Publisher / Repository:
- American Physical Society
- Date Published:
- Journal Name:
- PRX Life
- Volume:
- 4
- Issue:
- 2
- ISSN:
- 2835-8279
- Subject(s) / Keyword(s):
- Learning and adaptation without a brain, living and active matter, biological information processing
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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