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

Autor: Robertson N; Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK., Shchepachev V; The Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK., Wright D; Ashworth Laboratories, Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, UK., Turowski TW; Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK., Spanos C; Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK., Helwak A; Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK., Zamoyska R; Ashworth Laboratories, Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, UK., Tollervey D; Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK. D.Tollervey@ed.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Feb 03; Vol. 13 (1), pp. 649. Date of Electronic Publication: 2022 Feb 03.
DOI: 10.1038/s41467-022-28295-8
Abstrakt: 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 (70 AG in RMRP) show specifically impaired pre-rRNA processing, resulting in reduced mature rRNA and a reduced ratio of cytosolic to mitochondrial ribosomes. Moreover, the 70 AG mutation caused a reduction in intact RNase MRP complexes. Together, these results indicate that CHH is a ribosomopathy.
(© 2022. The Author(s).)
Databáze: MEDLINE
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