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

Lin-Tai Da, Fátima Pardo-Avila, Liang Xu, Daniel-Adriano Silva, Lu Zhang, Xin Gao, Dong Wang () and Xuhui Huang ()
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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
Daniel-Adriano Silva: School of Science and Institute for Advance Study, Hong Kong University of Science and Technology, Clear Water Bay
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
Xuhui Huang: School of Science and Institute for Advance Study, Hong Kong University of Science and Technology, Clear Water Bay

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11244

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