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 Dickson; Razq Hakem; Jack F Greenblatt; Stephen Lee; Alexander J R Bishop; Karim Mekhail

doi:10.1038/s41586-020-2497-0

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Nucleolar RNA polymerase II drives ribosome biogenesis

Journal article

Open access

Peer reviewed

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, …

Nature (London), Vol.585(7824), pp.298-302

2020-09

DOI: https://doi.org/10.1038/s41586-020-2497-0

PMID: 32669707

Abstract

RNA Helicases - metabolism

Protein Biosynthesis

Cell Nucleolus - physiology

Humans

Sarcoma, Ewing - pathology

Ribosomes - metabolism

RNA Polymerase I - metabolism

RNA Polymerase II - metabolism

Multifunctional Enzymes - metabolism

RNA, Untranslated - genetics

CRISPR-Associated Protein 9 - genetics

RNA Polymerase I - antagonists & inhibitors

CRISPR-Associated Protein 9 - metabolism

DNA, Ribosomal - genetics

Cell Nucleolus - genetics

Ribosomes - chemistry

DNA, Intergenic - genetics

DNA Helicases - metabolism

R-Loop Structures

Ribosomes - genetics

RNA, Untranslated - biosynthesis

Cell Line, Tumor

Cell Nucleolus - enzymology

Sarcoma, Ewing - genetics

Ribonuclease H - metabolism

Proteins are manufactured by ribosomes-macromolecular complexes of protein and RNA molecules that are assembled within major nuclear compartments called nucleoli . 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.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.152 Molecular & Cell Biology - DNA Damage; 1.152.257 DSBs
Web Of Science research areas: Multidisciplinary Sciences
ESI research areas: Molecular Biology & Genetics

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Title: Nucleolar RNA polymerase II drives ribosome biogenesis
Creators: Karan J Abraham - Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Negin Khosraviani - Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Janet N Y Chan - Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Aparna Gorthi - Greehey Children's Cancer Research Institute, Department of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX, USA
Anas Samman - Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Dorothy Y Zhao - Donnelly Centre, University of Toronto, Toronto, Ontario, Canada
Miling Wang - Sylvester Comprehensive Cancer Center, Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA
Michael Bokros - Sylvester Comprehensive Cancer Center, Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA
Elva Vidya - Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Lauren A Ostrowski - Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Roxanne Oshidari - Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Violena Pietrobon - Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Parasvi S Patel - Princess Margaret Cancer Research Centre, University Health Network, and Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Arash Algouneh - Princess Margaret Cancer Research Centre, University Health Network, and Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Rajat Singhania - Princess Margaret Cancer Research Centre, University Health Network, and Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Yupeng Liu - Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
V Talya Yerlici - Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Daniel D De Carvalho - Princess Margaret Cancer Research Centre, University Health Network, and Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Michael Ohh - Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Brendan C Dickson - Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
Razq Hakem - Princess Margaret Cancer Research Centre, University Health Network, and Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Jack F Greenblatt - Donnelly Centre, University of Toronto, Toronto, Ontario, Canada
Stephen Lee - Sylvester Comprehensive Cancer Center, Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA
Alexander J R Bishop - Mays Cancer Center, University of Texas Health at San Antonio, San Antonio, TX, USA
Karim Mekhail - Canada Research Chairs Program, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. karim.mekhail@utoronto.ca
Publication Details: Nature (London), Vol.585(7824), pp.298-302
Publisher: England
Grant note: P30 CA054174 / NCI NIH HHS T32 CA148724 / NCI NIH HHS R01 GM115342 / NIGMS NIH HHS TL1 TR002647 / NCATS NIH HHS R01 CA152063 / NCI NIH HHS R01 CA241554 / NCI NIH HHS K22 ES012264 / NIEHS NIH HHS R01 CA200676 / NCI NIH HHS
Academic Unit: Miller School of Medicine; Biochemistry & Molecular Biology Research
Language: English
Resource Type: Journal article
PMID: 32669707
Record Identifier: 991031576384102976