A Comprehensive mechanism for 5-carboxylcytosine induced transcriptional pausing revealed by Markov state models
AuthorsKonovalov, Kirill A.
Goonetilleke, Eshani C.
KAUST DepartmentComputer Science Program
Computational Bioscience Research Center (CBRC)
Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
Permanent link to this recordhttp://hdl.handle.net/10754/669503
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AbstractRNA 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, due to 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 the 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) since 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.
CitationKonovalov, K. A., Wang, W., Wang, G., Goonetilleke, E. C., Gao, X., Wang, D., & Huang, X. (2021). A Comprehensive mechanism for 5-carboxylcytosine induced transcriptional pausing revealed by Markov state models. Journal of Biological Chemistry, 100735. doi:10.1016/j.jbc.2021.100735
SponsorsThis work was supported by Hong Kong Research Grant Council (Grant numbers: 16302214, 16307718, 16303919, T13-605/18-W, AoE/M-09/12, and AoE/P-705/16 to X. H. and PF16-06144 to K. A. K.); Innovation and Technology Commission (Grant numbers: ITCPD/17-9 and ITC-CNERC14SC01 to X.H.); University of California San Diego start-up fund to D. W.; King Abdullah University of Science and Technology Office of Sponsored Research (Grant numbers: FCC/1/1976-23, FCC/1/1976-26, URF/1/4098-01-01, and REI/1/0018-01-01 to X.G.); Hong Kong Research Grant Council Collaborative Research Fund: (C6021-19EF to X. H.).
JournalJournal of Biological Chemistry
Except where otherwise noted, this item's license is described as This is an open access article under the CC BY license.
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