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Bridge helix bending promotes RNA polymerase II backtracking through a critical and conserved threonine residue

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  • Lin-Tai Da

    (School of Science and Institute for Advance Study, Hong Kong University of Science and Technology, Clear Water Bay)

  • Fátima Pardo-Avila

    (School of Science and Institute for Advance Study, Hong Kong University of Science and Technology, Clear Water Bay)

  • Liang Xu

    (Department of Cellular and Molecular Medicine, School of Medicine
    Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego)

  • Daniel-Adriano Silva

    (School of Science and Institute for Advance Study, Hong Kong University of Science and Technology, Clear Water Bay
    University of Washington)

  • Lu Zhang

    (School of Science and Institute for Advance Study, Hong Kong University of Science and Technology, Clear Water Bay)

  • Xin Gao

    (King Abdullah University of Science and Technology, Computational Bioscience Research Center, Computer)

  • Dong Wang

    (Department of Cellular and Molecular Medicine, School of Medicine
    Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego)

  • Xuhui Huang

    (School of Science and Institute for Advance Study, Hong Kong University of Science and Technology, Clear Water Bay
    School of Science and Institute for Advance Study, Hong Kong University of Science and Technology, Clear Water Bay
    Center of Systems Biology and Human Health, School of Science and Institute for Advance Study, Hong Kong University of Science and Technology, Clear Water Bay)

Abstract

The dynamics of the RNA polymerase II (Pol II) backtracking process is poorly understood. We built a Markov State Model from extensive molecular dynamics simulations to identify metastable intermediate states and the dynamics of backtracking at atomistic detail. Our results reveal that Pol II backtracking occurs in a stepwise mode where two intermediate states are involved. We find that the continuous bending motion of the Bridge helix (BH) serves as a critical checkpoint, using the highly conserved BH residue T831 as a sensing probe for the 3′-terminal base paring of RNA:DNA hybrid. If the base pair is mismatched, BH bending can promote the RNA 3′-end nucleotide into a frayed state that further leads to the backtracked state. These computational observations are validated by site-directed mutagenesis and transcript cleavage assays, and provide insights into the key factors that regulate the preferences of the backward translocation.

Suggested Citation

  • Lin-Tai Da & Fátima Pardo-Avila & Liang Xu & Daniel-Adriano Silva & Lu Zhang & Xin Gao & Dong Wang & Xuhui Huang, 2016. "Bridge helix bending promotes RNA polymerase II backtracking through a critical and conserved threonine residue," Nature Communications, Nature, vol. 7(1), pages 1-10, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11244
    DOI: 10.1038/ncomms11244
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    Cited by:

    1. Bojun Liu & Jordan G. Boysen & Ilona Christy Unarta & Xuefeng Du & Yixuan Li & Xuhui Huang, 2025. "Exploring transition states of protein conformational changes via out-of-distribution detection in the hyperspherical latent space," Nature Communications, Nature, vol. 16(1), pages 1-12, December.

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