Nucleolar RNA polymerase II drives ribosome biogenesis

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 Pietrobon, Parasvi S. Patel, Arash Algouneh, Rajat Singhania, Yupeng Liu, V. Talya Yerlici, Daniel D. Carvalho, Michael Ohh, Brendan C. Dickson, Razq Hakem, Jack F. Greenblatt, Stephen Lee, Alexander J. R. Bishop and Karim Mekhail ()
Additional contact information
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
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
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
Brendan C. Dickson: University of Toronto
Razq Hakem: University of Toronto
Jack F. Greenblatt: University of Toronto
Stephen Lee: University of Miami
Alexander J. R. Bishop: University of Texas Health at San Antonio
Karim Mekhail: University of Toronto

Nature, 2020, vol. 585, issue 7824, 298-302

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2497-0

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