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

Nic Robertson, Vadim Shchepachev, David Wright, Tomasz W. Turowski, Christos Spanos, Aleksandra Helwak, Rose Zamoyska and David Tollervey ()
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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

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28295-8

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