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. De Carvalho, Michael Ohh, Brendan C. DicksonRazq Hakem, Jack F. Greenblatt, Stephen Lee, Alexander J.R. Bishop, Karim Mekhail

Research output: Contribution to journalArticlepeer-review

68 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)298-302
Number of pages5
Issue number7824
StatePublished - Sep 10 2020

ASJC Scopus subject areas

  • General


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