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Abstract
rRNA post transcriptional modifications play a role in cancer development by affecting ribosomal function. In particular, the snoRNA U50, mediating the methylation of C2848 in 28S rRNA, has been suggested as a potential tumor suppressor-like gene playing a role in breast and prostate cancers and B-cell lymphoma. Indeed, we observed the downregulation of U50 in colon cancer cell lines as well as tumors. We then investigated the relationship between U50 and proliferation in lymphocytes stimulated by phytohemagglutinin (PHA) and observed a strong decrease in U50 levels associated with a reduced C2848 methylation. This reduction was due to an alteration of U50 stability and to an increase of its consumption. Indeed, the blockade of ribosome biogenesis induced only an early decrease in U50 followed by a stabilization of U50 levels when ribosome biogenesis was almost completely blocked. Similar results were found with other snoRNAs. Lastly, we observed that U50 modulation affects ribosome efficiency in IRES-mediated translation, demonstrating that changes in the methylation levels of a single specific site on 28S rRNA may alter ribosome function. In conclusion, our results link U50 to the cellular proliferation rate and ribosome biogenesis and these findings may explain why its levels are often greatly reduced in cancers.
Highlights
Ribosome biogenesis is a highly coordinated process occurring in the nucleolus, where a polycistronic pre-ribosomal RNA transcript is processed to generate the mature 18S, 5.8S, and 28S rRNA
We found that U50 was downregulated in tumor tissues if compared to the normal counterpart and this reduction was statistically significant in a subgroup of low-stage tumors (p = 0.047) (Figure 1A, left)
We found that U50 expression is highly variable between lines, but always lower than normal colon tissues (NT) (Figure 1B, left), while the overall comparison between NT and colon cancer cell lines showed a statistically significant difference for U50 expression (p = 0.0004) (Figure 1B, right-top)
Summary
Ribosome biogenesis is a highly coordinated process occurring in the nucleolus, where a polycistronic pre-ribosomal RNA (pre-rRNA) transcript is processed to generate the mature 18S, 5.8S, and 28S rRNA. The development of three-dimensional maps of the modified nucleotides in the ribosomes of Escherichia coli and yeast has revealed that rRNA modifications occur in conserved and functionally important regions for subunit–subunit and nascent protein interactions, for tRNA and mRNA binding, but not in those interacting with proteins (see [12,13]). This correlation indicates that modifications influence both the structure and the function of the ribosome [14]. In this paper we investigated the relationship between snoU50 and cancer in colon cancer cell lines and tumors with particular regard to proliferation
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