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

Roberston, N., Shchepachev, V., Wright, D., Turowski, T.W., Spanos, C., Helwak, A., Zamoyska, R. and Tollervey, D.

Nature Communications (2022) 13, 649

Mutations in the human lncRNA, RMRP, cause Cartilage Hair Hypoplasia, with skeletal abnormalities and impaired immune response. Here, disease linked mutations are shown to impair pre-rRNA processing, ribosome accumulation and T cell activation.

Summary of Paper by Lori Koch

Ribosomes are large and abundant structures within the cell that synthesize new protein. Ribosomal RNAs (rRNAs) form the core parts of the ribosome and perform key functions in protein synthesis. In their recent publication in Nature Communications, scientists in the Tollervey group, led by Nic Robertson, report results which demonstrate that disease-associated mutations in the gene RMRP compromise ribosome synthesis. The long, noncoding RNA RMRP provides the core of an RNA-complex with RNA cleavage activity - RNase MRP. Mutations in RMRP are associated with Cartilage Hair Hypoplasia (CHH) syndrome, which causes reduced life expectancy due to immunodeficiency. The scientists disrupted RMRP using CRISPR in mice and found that this reduced T-cell expansion, which must occur during immune response. They also analysed the RNA from the mutant T-cells and identified an accumulation of rRNA intermediate molecules, suggesting that it wasn’t being properly converted into its shorter, final forms. Next, the scientists generated human cell lines expressing RMRP with the most common human disease-related mutation and found that these also contained an excess of intermediate-length rRNA precursor molecules. A similar defect was found in CHH patient-derived fibroblasts. Hypothesizing that the total number of ribosomes in mutant cells may be affected, the scientists used the TRAPP method in human cells to quantify all RNA-associated proteins - in wild-type cells versus cells with the RMRP mutation. This demonstrated that RMRP mutants have an abnormally low number of ribosomes in the cytoplasm compared to mitochondrial ribosomes, which do not rely on RNase MRP. Together, the results indicate that CHH arises from defects in the processing of the rRNA leading to reduced ribosome abundance - termed a ribosomopathy - and that this compromises T-cell expansion. 

Journal Link:


Additional Links: