A non-canonical role for a small nucleolar RNA in ribosome biogenesis and oncogene-induced senescence
Introduction
The canonical function of small nucleolar RNAs (snoRNAs) is to guide the chemical modification of other RNAs, mainly ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), and small nuclear RNAs (snRNAs). However, accumulating evidence suggests that snoRNAs may have additional functions.
Methods
We performed a genome-wide CRISPR screen to identify noncoding RNAs that are required for oncogene-induced senescence (OIS), a major mechanism of tumor suppression.
Results
These experiments revealed that a highly conserved H/ACA box snoRNA that guides the pseudouridylation of 18S rRNA is required for OIS. We demonstrated that loss of this snoRNA has little effect on translation. Rather, loss of the snoRNA strongly increased 60S ribosomal subunit biogenesis. Interestingly, oncogenic stress has been shown to perturb ribosome biogenesis, resulting in the accumulation of free ribosomal proteins (RPs) that bind and inhibit MDM2, leading to activation of the p53 pathway. We showed that the snoRNA interacts directly with a large ribosomal subunit protein, decreasing its incorporation into maturing 60S subunits and increasing the pool of free RPs, thereby activating the RP-MDM2-p53 pathway and the senescence program.
Conclusion
Altogether, these findings reveal a snoRNA that regulates ribosome biogenesis and the p53-mediated ribosomal stress response through a non-canonical mechanism distinct from its role in guiding rRNA modification.