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Nucleolar RNA polymerase II drives ribosome biogenesis

Author

Listed:
  • Karan J. Abraham

    (University of Toronto)

  • Negin Khosraviani

    (University of Toronto)

  • Janet N. Y. Chan

    (University of Toronto)

  • Aparna Gorthi

    (University of Texas Health at San Antonio)

  • Anas Samman

    (University of Toronto)

  • Dorothy Y. Zhao

    (University of Toronto
    University of Toronto)

  • Miling Wang

    (University of Miami)

  • Michael Bokros

    (University of Miami)

  • Elva Vidya

    (University of Toronto)

  • Lauren A. Ostrowski

    (University of Toronto)

  • Roxanne Oshidari

    (University of Toronto)

  • Violena Pietrobon

    (University of Toronto)

  • Parasvi S. Patel

    (University of Toronto)

  • Arash Algouneh

    (University of Toronto
    University of Toronto)

  • Rajat Singhania

    (University of Toronto)

  • Yupeng Liu

    (University of Toronto)

  • V. Talya Yerlici

    (University of Toronto)

  • Daniel D. Carvalho

    (University of Toronto)

  • Michael Ohh

    (University of Toronto
    University of Toronto)

  • Brendan C. Dickson

    (University of Toronto
    Mount Sinai Hospital)

  • Razq Hakem

    (University of Toronto)

  • Jack F. Greenblatt

    (University of Toronto
    University of Toronto)

  • Stephen Lee

    (University of Miami)

  • Alexander J. R. Bishop

    (University of Texas Health at San Antonio
    University of Texas Health at San Antonio)

  • Karim Mekhail

    (University of Toronto
    University of Toronto)

Abstract

Proteins are manufactured by ribosomes—macromolecular complexes of protein and RNA molecules that are assembled within major nuclear compartments called nucleoli1,2. Existing models suggest that RNA polymerases I and III (Pol I and Pol III) are the only enzymes that directly mediate the expression of the ribosomal RNA (rRNA) components of ribosomes. Here we show, however, that RNA polymerase II (Pol II) inside human nucleoli operates near genes encoding rRNAs to drive their expression. Pol II, assisted by the neurodegeneration-associated enzyme senataxin, generates a shield comprising triplex nucleic acid structures known as R-loops at intergenic spacers flanking nucleolar rRNA genes. The shield prevents Pol I from producing sense intergenic noncoding RNAs (sincRNAs) that can disrupt nucleolar organization and rRNA expression. These disruptive sincRNAs can be unleashed by Pol II inhibition, senataxin loss, Ewing sarcoma or locus-associated R-loop repression through an experimental system involving the proteins RNaseH1, eGFP and dCas9 (which we refer to as ‘red laser’). We reveal a nucleolar Pol-II-dependent mechanism that drives ribosome biogenesis, identify disease-associated disruption of nucleoli by noncoding RNAs, and establish locus-targeted R-loop modulation. Our findings revise theories of labour division between the major RNA polymerases, and identify nucleolar Pol II as a major factor in protein synthesis and nuclear organization, with potential implications for health and disease.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:nature:v:585:y:2020:i:7824:d:10.1038_s41586-020-2497-0
    DOI: 10.1038/s41586-020-2497-0
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    Cited by:

    1. Negin Khosraviani & V. Talya Yerlici & Jonathan St-Germain & Yi Yang Hou & Shi Bo Cao & Carla Ghali & Michael Bokros & Rehna Krishnan & Razqallah Hakem & Stephen Lee & Brian Raught & Karim Mekhail, 2024. "Nucleolar Pol II interactome reveals TBPL1, PAF1, and Pol I at intergenic rDNA drive rRNA biogenesis," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Wen Juan Tu & Michelle Melino & Jenny Dunn & Robert D. McCuaig & Helle Bielefeldt-Ohmann & Sofiya Tsimbalyuk & Jade K. Forwood & Taniya Ahuja & John Vandermeide & Xiao Tan & Minh Tran & Quan Nguyen & , 2023. "In vivo inhibition of nuclear ACE2 translocation protects against SARS-CoV-2 replication and lung damage through epigenetic imprinting," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    3. 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.

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