Kinetic mechanisms for the sequence dependence of transcriptional errors

• 成果类型: Article
• 署名作者: Midha, Tripti; Kolomeisky, Anatoly B.; Igoshin, Oleg A.
• 署名单位: Rice University; Rice University; Rice University; Rice University; Rice University; Rice University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14271
• DOI: 10.1073/pnas.2505040122
• 发表日期: 2025-07-15
• 关键词: rna-polymerase-ii; FIDELITY; dna; elongation; proteins; binding

摘要

The fidelity of template-dependent mRNA synthesis during transcription elongationis the primary determinant of accurate gene expression and the maintenance offunctional RNA transcripts. However, the mechanisms governing transcription fidelityremain incompletely understood. While previous studies have characterized how errorrates vary with nucleotide identity at upstream and downstream positions fromthe incorporation site, the comprehensive microscopic explanation of this sequencedependence has not been elucidated. In this study, we develop a theoretical approachthat integrates transcription proofreading mechanisms and inhomogeneous DNAsequence effects. Using first-passage analysis validated by Monte Carlo simulations,we quantitatively characterize nucleotide-specific error rates during RNA polymeraseII transcription. The model accurately reproduces experimental error rates and predictskinetic parameters influencing transcriptional fidelity. Analysis reveals nucleotideincorporation rates follow the hierarchy U