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.
Highlights
RMRP encodes a non-coding RNA forming the core of the RNase MRP ribonucleoprotein complex
In this study we show that mutations in RMRP impair mouse T-cell activation and delay pre-ribosomal RNA (rRNA) processing, a phenotype recapitulated in patient-derived human fibroblasts
Activating T cells require high rates of ribosome synthesis to support rapid cell division[6]. We hypothesized that this might confer particular vulnerability to partial disruption of RMRP function if its primary biological role is in pre-rRNA processing
Summary
RMRP encodes a non-coding RNA forming the core of the RNase MRP ribonucleoprotein complex. Human cells engineered with the most common CHH mutation (70AG in RMRP) show impaired pre-rRNA processing, resulting in reduced mature rRNA and a reduced ratio of cytosolic to mitochondrial ribosomes. Human rRNAs are transcribed by RNA polymerase I (RNAPI) as a long precursor, 47 S pre-rRNA (Supplementary Fig. 1) This polycistronic transcript includes the 18 S rRNA, destined for the small ribosomal subunit (SSU), and the 5.8 S and 28 S rRNA components of the large subunit (LSU)[8]. The 47 S primary transcript undergoes a complex sequence of endonuclease cleavages and exonuclease digestion steps that remove the spacer regions These process the 47 S RNA through a series of discrete pre-rRNA processing intermediates (Supplementary Fig. 1), to generate the mature rRNAs (Fig. 1A). The existence of partially redundant pathways may enhance the overall efficiency and resilience of the system
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