Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 296, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.jbc.2021.100735
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Funding
- Hong Kong Research Grant Council [16302214, 16307718, 16303919, T13-605/18-W, AoE/M-09/12, AoE/P705/16, PF16-06144]
- Innovation and Technology Commission [ITCPD/17-9, ITC-CNERC14SC01]
- University of California San Diego
- King Abdullah University of Science and Technology Office of Sponsored Research [FCC/1/1976-23, FCC/1/1976-26, URF/1/4098-01-01, REI/1/0018-01-01]
- Hong Kong Research Grant Council Collaborative Research Fund [C6021-19EF]
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Epigenetic modification 5-carboxycytosine (5caC) in the genome can induce transcription pauses by impacting the translocation process of Pol II.
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.
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