A comprehensive mechanism for 5-carboxylcytosine-induced transcriptional pausing revealed by Markov state models
| Autor: | Xin Gao, Wei Wang, Xuhui Huang, Guo Wang, Kirill A. Konovalov, Eshani Chrisana Goonetilleke, Dong Wang |
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| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Transcriptional Activation 0301 basic medicine Saccharomyces cerevisiae Proteins Transcription Genetic DNA repair 5caC 5-carboxycytosine RNA polymerase II Saccharomyces cerevisiae Biochemistry tICA time-lagged independent component analysis Epigenesis Genetic Cytosine 03 medical and health sciences chemistry.chemical_compound Transcription (biology) MSM Markov state model GMRQ generalized matrix Rayleigh quotient Epigenetics Molecular Biology Pol II RNA polymerase II Models Genetic 030102 biochemistry & molecular biology biology MCMC Markov chain Monte Carlo Active site Cell Biology FL3 fork loop 3 Markov Chains genomic DNA 030104 developmental biology chemistry Mutation biology.protein Biophysics RNA Polymerase II DNA Research Article |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| DOI: | 10.1016/j.jbc.2021.100735 |
| Popis: | RNA polymerase II (Pol II) surveils the genome, pausing as it encounters DNA lesions and base modifications and initiating signals for DNA repair among other important regulatory events. Recent work suggests that Pol II pauses at 5-carboxycytosine (5caC), an epigenetic modification of cytosine, because of a specific hydrogen bond between the carboxyl group of 5caC and a specific residue in fork loop 3 of Pol II. This hydrogen bond compromises productive NTP binding and slows down elongation. Apart from this specific interaction, the carboxyl group of 5caC can potentially interact with numerous charged residues in the cleft of Pol II. However, it is not clear how other interactions between Pol II and 5caC contribute to pausing. In this study, we use Markov state models (a type of kinetic network models) built from extensive molecular dynamics simulations to comprehensively study the impact of 5caC on Pol II translocation. We describe two translocation intermediates with specific interactions that prevent the template base from loading into the Pol II active site. In addition to the previously observed state with 5caC constrained by fork loop 3, we discovered a new intermediate state with a hydrogen bond between 5caC and fork loop 2. Surprisingly, we find that 5caC may curb translocation by suppressing kinking of the helix bordering the active site (the bridge helix) because its high flexibility is critical to translocation. Our work provides new insights into how epigenetic modifications of genomic DNA can modulate Pol II translocation, inducing pauses in transcription. |
| Databáze: | OpenAIRE |
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