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Nat Commun. 2016 Aug 19;7:12429. doi: 10.1038/ncomms12429.

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

Author information

1
Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich, 81337 Munich, Germany.
2
LIFE-Leipzig Research Center for Civilization Diseases, Universität Leipzig, 04103 Leipzig, Germany.
3
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
4
Department of Vascular and Endovascular Surgery, Ludwig-Maximilians-University Munich, 81337 Munich, Germany.
5
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, 04103 Leipzig, Germany.
6
Institute for Medical Informatics, Statistics and Epidemiology, University Leipzig, 04107 Leipzig, Germany.
7
Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
8
Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
9
Interdisciplinary Center for Clinical Research, University Leipzig, 04103 Leipzig, Germany.

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.

PMID:
27539542
PMCID:
PMC4992165
DOI:
10.1038/ncomms12429
[Indexed for MEDLINE]
Free PMC Article

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