A disease-linked lncRNA mutation in RNase MRP inhibits ribosome synthesis
| Autor: | Nic Robertson, Vadim Shchepachev, David Wright, Tomasz W. Turowski, Christos Spanos, Aleksandra Helwak, Rose Zamoyska, David Tollervey |
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| Přispěvatelé: | Shchepachev, Vadim [0000-0001-8551-5940], Turowski, Tomasz W [0000-0002-7052-8682], Spanos, Christos [0000-0002-4376-8242], Zamoyska, Rose [0000-0001-9816-2638], Tollervey, David [0000-0003-2894-2772], Apollo - University of Cambridge Repository |
| Rok vydání: | 2021 |
| Předmět: |
RNA Folding
Ribosomopathy T-Lymphocytes General Physics and Astronomy 13 medicine.disease_cause Ribosome RNA Precursors 42/41 Mitochondrial ribosome Cells Cultured Mice Knockout Mutation Multidisciplinary Chemistry article Cell biology 13/31 631/337/384/2568 RNA Long Noncoding 631/80/304 Primary Immunodeficiency Diseases Science 631/250/2502 38/90 13/106 Osteochondrodysplasias General Biochemistry Genetics and Molecular Biology 38 38/91 Endoribonucleases 631/208/200 medicine Animals Humans Hirschsprung Disease RRNA processing Gene Cell Proliferation Base Sequence 82/58 RNA General Chemistry Fibroblasts 49 Mice Inbred C57BL RNase MRP RNA Ribosomal 631/1647/2017/2003 K562 Cells Ribosomes Hair |
| Zdroj: | Nature Communications, Vol 13, Iss 1, Pp 1-14 (2022) Robertson, N, Shchepachev, V, Wright, D, Turowski, T W, Spanos, C, Helwak, A, Zamoyska, R & Tollervey, D 2022, ' A disease-linked lncRNA mutation in RNase MRP inhibits ribosome synthesis ', Nature Communications, vol. 13, no. 1, 649 . https://doi.org/10.1038/s41467-022-28295-8 |
| DOI: | 10.21203/rs.3.rs-491952/v1 |
| Popis: | 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, and the first processing-specific human disorder to be described.HighlightsMutations in RMRP lncRNA impair pre-rRNA processing and T cell activationPatient derived fibroblasts show impaired pre-rRNA processingCells with the most common disease-linked mutation have specific processing defectsCytoplasmic ribosomes and intact RNase MRP complexes are also reduced in these cells |
| Databáze: | OpenAIRE |
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