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A small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II

Author

Listed:
  • Yanli Liu

    (Soochow University
    Central China Normal University
    University of Toronto)

  • Aman Iqbal

    (University of Toronto)

  • Weiguo Li

    (Central China Normal University
    University of Toronto)

  • Zuyao Ni

    (University of Toronto)

  • Yalong Wang

    (The University of Texas MD Anderson Cancer Center)

  • Jurupula Ramprasad

    (Soochow University)

  • Karan Joshua Abraham

    (University of Toronto)

  • Mengmeng Zhang

    (Soochow University)

  • Dorothy Yanling Zhao

    (University of Toronto)

  • Su Qin

    (University of Toronto
    Southern University of Science and Technology)

  • Peter Loppnau

    (University of Toronto)

  • Honglv Jiang

    (Soochow University)

  • Xinghua Guo

    (University of Toronto)

  • Peter J. Brown

    (University of Toronto)

  • Xuechu Zhen

    (Soochow University)

  • Guoqiang Xu

    (Soochow University)

  • Karim Mekhail

    (University of Toronto)

  • Xingyue Ji

    (Soochow University)

  • Mark T. Bedford

    (The University of Texas MD Anderson Cancer Center)

  • Jack F. Greenblatt

    (University of Toronto)

  • Jinrong Min

    (Central China Normal University
    University of Toronto
    University of Toronto)

Abstract

Survival of motor neuron (SMN) functions in diverse biological pathways via recognition of symmetric dimethylarginine (Rme2s) on proteins by its Tudor domain, and deficiency of SMN leads to spinal muscular atrophy. Here we report a potent and selective antagonist with a 4-iminopyridine scaffold targeting the Tudor domain of SMN. Our structural and mutagenesis studies indicate that both the aromatic ring and imino groups of compound 1 contribute to its selective binding to SMN. Various on-target engagement assays support that compound 1 specifically recognizes SMN in a cellular context and prevents the interaction of SMN with the R1810me2s of RNA polymerase II subunit POLR2A, resulting in transcription termination and R-loop accumulation mimicking SMN depletion. Thus, in addition to the antisense, RNAi and CRISPR/Cas9 techniques, potent SMN antagonists could be used as an efficient tool to understand the biological functions of SMN.

Suggested Citation

  • Yanli Liu & Aman Iqbal & Weiguo Li & Zuyao Ni & Yalong Wang & Jurupula Ramprasad & Karan Joshua Abraham & Mengmeng Zhang & Dorothy Yanling Zhao & Su Qin & Peter Loppnau & Honglv Jiang & Xinghua Guo & , 2022. "A small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33229-5
    DOI: 10.1038/s41467-022-33229-5
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    References listed on IDEAS

    as
    1. Karan J. Abraham & Negin Khosraviani & Janet N. Y. Chan & Aparna Gorthi & Anas Samman & Dorothy Y. Zhao & Miling Wang & Michael Bokros & Elva Vidya & Lauren A. Ostrowski & Roxanne Oshidari & Violena P, 2020. "Nucleolar RNA polymerase II drives ribosome biogenesis," Nature, Nature, vol. 585(7824), pages 298-302, September.
    2. Yanli Liu & Su Qin & Tsai-Yu Chen & Ming Lei & Shilpa S. Dhar & Jolene Caifeng Ho & Aiping Dong & Peter Loppnau & Yanjun Li & Min Gyu Lee & Jinrong Min, 2019. "Structural insights into trans-histone regulation of H3K4 methylation by unique histone H4 binding of MLL3/4," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    3. Dorothy Yanling Zhao & Gerald Gish & Ulrich Braunschweig & Yue Li & Zuyao Ni & Frank W. Schmitges & Guoqing Zhong & Ke Liu & Weiguo Li & Jason Moffat & Masoud Vedadi & Jinrong Min & Tony J. Pawson & B, 2016. "SMN and symmetric arginine dimethylation of RNA polymerase II C-terminal domain control termination," Nature, Nature, vol. 529(7584), pages 48-53, January.
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    Cited by:

    1. Lennart Enders & Marton Siklos & Jan Borggräfe & Stefan Gaussmann & Anna Koren & Monika Malik & Tatjana Tomek & Michael Schuster & Jiří Reiniš & Elisa Hahn & Andrea Rukavina & Andreas Reicher & Tamara, 2023. "Pharmacological perturbation of the phase-separating protein SMNDC1," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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