A disease-linked lncRNA mutation in RNase MRP inhibits ribosome synthesis.
Springer Science and Business Media LLC
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Robertson, N., Shchepachev, V., Wright, D., Turowski, T. W., Spanos, C., Helwak, A., Zamoyska, R., & et al. (2022). A disease-linked lncRNA mutation in RNase MRP inhibits ribosome synthesis.. Nat Commun, 13 (1) https://doi.org/10.1038/s41467-022-28295-8
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.
Article, /631/208/200, /631/80/304, /631/250/2502, /631/1647/2017/2003, /631/337/384/2568, /38, /38/90, /38/91, /49, /13/31, /42/41, /82/58, /13, /13/106, article
Wellcome Trust (Wellcome) (205014, 077248, 203149)
External DOI: https://doi.org/10.1038/s41467-022-28295-8
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333601