title: Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans.
abstract: Circular RNAs (circRNAs) are broadly expressed in eukaryotic cells, but their molecular mechanism in human disease remains obscure. Here we show that circular antisense non-coding RNA in the INK4 locus (circANRIL), which is transcribed at a locus of atherosclerotic cardiovascular disease on chromosome 9p21, confers atheroprotection by controlling ribosomal RNA (rRNA) maturation and modulating pathways of atherogenesis. CircANRIL binds to pescadillo homologue 1 (PES1), an essential 60S-preribosomal assembly factor, thereby impairing exonuclease-mediated pre-rRNA processing and ribosome biogenesis in vascular smooth muscle cells and macrophages. As a consequence, circANRIL induces nucleolar stress and p53 activation, resulting in the induction of apoptosis and inhibition of proliferation, which are key cell functions in atherosclerosis. Collectively, these findings identify circANRIL as a prototype of a circRNA regulating ribosome biogenesis and conferring atheroprotection, thereby showing that circularization of long non-coding RNAs may alter RNA function and protect from human disease.
authors.affiliation: Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich, 81337 Munich, Germany.|LIFE-Leipzig Research Center for Civilization Diseases, Universität Leipzig, 04103 Leipzig, Germany.
authors.forename: Lesca M
authors.initials: LM
authors.lastname: Holdt
authors.affiliation: Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich, 81337 Munich, Germany.
authors.forename: Anika
authors.initials: A
authors.lastname: Stahringer
authors.affiliation: Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich, 81337 Munich, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Sass
authors.affiliation: Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
authors.forename: Garwin
authors.initials: G
authors.lastname: Pichler
authors.affiliation: Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
authors.forename: Nils A
authors.initials: NA
authors.lastname: Kulak
authors.affiliation: Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich, 81337 Munich, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wilfert
authors.affiliation: Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich, 81337 Munich, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kohlmaier
authors.affiliation: Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich, 81337 Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Herbst
authors.affiliation: Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich, 81337 Munich, Germany.
authors.forename: Bernd H
authors.initials: BH
authors.lastname: Northoff
authors.affiliation: Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich, 81337 Munich, Germany.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Nicolaou
authors.affiliation: Department of Vascular and Endovascular Surgery, Ludwig-Maximilians-University Munich, 81337 Munich, Germany.
authors.forename: Gabor
authors.initials: G
authors.lastname: Gäbel
authors.affiliation: LIFE-Leipzig Research Center for Civilization Diseases, Universität Leipzig, 04103 Leipzig, Germany.|Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, 04103 Leipzig, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Beutner
authors.affiliation: LIFE-Leipzig Research Center for Civilization Diseases, Universität Leipzig, 04103 Leipzig, Germany.|Institute for Medical Informatics, Statistics and Epidemiology, University Leipzig, 04107 Leipzig, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Scholz
authors.affiliation: LIFE-Leipzig Research Center for Civilization Diseases, Universität Leipzig, 04103 Leipzig, Germany.|Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, 04103 Leipzig, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Thiery
authors.affiliation: Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Kiran
authors.initials: K
authors.lastname: Musunuru
authors.affiliation: LIFE-Leipzig Research Center for Civilization Diseases, Universität Leipzig, 04103 Leipzig, Germany.|Interdisciplinary Center for Clinical Research, University Leipzig, 04103 Leipzig, Germany.
authors.forename: Knut
authors.identifier: 0000-0001-8110-1273
authors.initials: K
authors.lastname: Krohn
authors.affiliation: Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mann
authors.affiliation: Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich, 81337 Munich, Germany.|LIFE-Leipzig Research Center for Civilization Diseases, Universität Leipzig, 04103 Leipzig, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Teupser
mesh_terms: D017209:Apoptosis; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002466:Cell Nucleolus / Q000378:metabolism; D049109:Cell Proliferation; D002899:Chromosomes, Human, Pair 9; D064112:Clustered Regularly Interspaced Short Palindromic Repeats; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D008264:Macrophages / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D012335:RNA, Ribosomal / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins
chemical_list: C000614131:CDKN2A protein, human; C561518:CDKN2B antisense RNA, human; C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; C484463:PES1 protein, human; D011506:Proteins; D062085:RNA, Long Noncoding; D012335:RNA, Ribosomal; D016601:RNA-Binding Proteins