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A disease-linked lncRNA mutation in RNase MRP inhibits ribosome synthesis

Author

Listed:
  • Nic Robertson

    (University of Edinburgh)

  • Vadim Shchepachev

    (University of Cambridge)

  • David Wright

    (University of Edinburgh)

  • Tomasz W. Turowski

    (University of Edinburgh)

  • Christos Spanos

    (University of Edinburgh)

  • Aleksandra Helwak

    (University of Edinburgh)

  • Rose Zamoyska

    (University of Edinburgh)

  • David Tollervey

    (University of Edinburgh)

Abstract

RMRP encodes a non-coding RNA forming the core of the RNase MRP ribonucleoprotein complex. Mutations cause Cartilage Hair Hypoplasia (CHH), characterized by skeletal abnormalities and impaired T cell activation. Yeast RNase MRP cleaves a specific site in the pre-ribosomal RNA (pre-rRNA) during ribosome synthesis. CRISPR-mediated disruption of RMRP in human cells lines caused growth arrest, with pre-rRNA accumulation. Here, we analyzed disease-relevant primary cells, showing that mutations in RMRP impair mouse T cell activation and delay pre-rRNA processing. Patient-derived human fibroblasts with CHH-linked mutations showed similar pre-rRNA processing delay. Human cells engineered with the most common CHH mutation (70AG in RMRP) show specifically impaired pre-rRNA processing, resulting in reduced mature rRNA and a reduced ratio of cytosolic to mitochondrial ribosomes. Moreover, the 70AG mutation caused a reduction in intact RNase MRP complexes. Together, these results indicate that CHH is a ribosomopathy.

Suggested Citation

  • Nic Robertson & Vadim Shchepachev & David Wright & Tomasz W. Turowski & Christos Spanos & Aleksandra Helwak & Rose Zamoyska & David Tollervey, 2022. "A disease-linked lncRNA mutation in RNase MRP inhibits ribosome synthesis," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28295-8
    DOI: 10.1038/s41467-022-28295-8
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    References listed on IDEAS

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    1. Mirjam Hunziker & Jonas Barandun & Elisabeth Petfalski & Dongyan Tan & Clémentine Delan-Forino & Kelly R. Molloy & Kelly H. Kim & Hywel Dunn-Davies & Yi Shi & Malik Chaker-Margot & Brian T. Chait & Th, 2016. "UtpA and UtpB chaperone nascent pre-ribosomal RNA and U3 snoRNA to initiate eukaryotic ribosome assembly," Nature Communications, Nature, vol. 7(1), pages 1-10, November.
    2. Rajagopal, 2014. "The Human Factors," Palgrave Macmillan Books, in: Architecting Enterprise, chapter 9, pages 225-249, Palgrave Macmillan.
    3. Anna Perederina & Di Li & Hyunwook Lee & Carol Bator & Igor Berezin & Susan L. Hafenstein & Andrey S. Krasilnikov, 2020. "Cryo-EM structure of catalytic ribonucleoprotein complex RNase MRP," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    4. Mazhar Adli, 2018. "The CRISPR tool kit for genome editing and beyond," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
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