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

Author

Listed:
  • Lesca M. Holdt

    (Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich
    LIFE—Leipzig Research Center for Civilization Diseases, Universität Leipzig)

  • 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
    Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig)

  • Markus Scholz

    (LIFE—Leipzig Research Center for Civilization Diseases, Universität Leipzig
    Institute for Medical Informatics, Statistics and Epidemiology, University Leipzig)

  • Joachim Thiery

    (LIFE—Leipzig Research Center for Civilization Diseases, Universität Leipzig
    Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig)

  • Kiran Musunuru

    (Perelman School of Medicine at the University of Pennsylvania
    Perelman School of Medicine at the University of Pennsylvania)

  • Knut Krohn

    (LIFE—Leipzig Research Center for Civilization Diseases, Universität Leipzig
    Interdisciplinary Center for Clinical Research, University Leipzig)

  • Matthias Mann

    (Max Planck Institute of Biochemistry)

  • Daniel Teupser

    (Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich
    LIFE—Leipzig Research Center for Civilization Diseases, Universität Leipzig)

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.

Suggested Citation

  • 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 & F, 2016. "Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans," Nature Communications, Nature, vol. 7(1), pages 1-14, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12429
    DOI: 10.1038/ncomms12429
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    Cited by:

    1. Maya Ron & Igor Ulitsky, 2022. "Context-specific effects of sequence elements on subcellular localization of linear and circular RNAs," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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