Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans

Lesca M. Holdt (), Anika Stahringer, Kristina Sass, Garwin Pichler, Nils A. Kulak, Wolfgang Wilfert, Alexander Kohlmaier, Andreas Herbst, Bernd H. Northoff, Alexandros Nicolaou, Gabor Gäbel, Frank Beutner, Markus Scholz, Joachim Thiery, Kiran Musunuru, Knut Krohn, Matthias Mann and Daniel Teupser ()
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Lesca M. Holdt: Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich
Anika Stahringer: Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich
Kristina Sass: Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich
Garwin Pichler: Max Planck Institute of Biochemistry
Nils A. Kulak: Max Planck Institute of Biochemistry
Wolfgang Wilfert: Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich
Alexander Kohlmaier: Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich
Andreas Herbst: Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich
Bernd H. Northoff: Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich
Alexandros Nicolaou: Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich
Gabor Gäbel: Ludwig-Maximilians-University Munich
Frank Beutner: LIFE—Leipzig Research Center for Civilization Diseases, Universität Leipzig
Markus Scholz: LIFE—Leipzig Research Center for Civilization Diseases, Universität Leipzig
Joachim Thiery: LIFE—Leipzig Research Center for Civilization Diseases, Universität Leipzig
Kiran Musunuru: Perelman School of Medicine at the University of Pennsylvania
Knut Krohn: LIFE—Leipzig Research Center for Civilization Diseases, Universität Leipzig
Matthias Mann: Max Planck Institute of Biochemistry
Daniel Teupser: Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12429

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