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Heterogeneity in Ribosomal RNA Base Modifications Modulate Lipid Metabolic Flux to Maintain a Tumor Suppressive Program

  • Author(s): Contreras, Adrian
  • Advisor(s): Ruggero, Davide
  • et al.
Abstract

It is now appreciated that both coding and non-coding RNAs contain a large variety of post-transcriptional nucleotide modifications that change the chemical composition of RNA. The RNA component of the ribosome, ribosomal RNA (rRNA) is the most abundant type of RNA in all domain of life and contains the highest amount of base modifications, however the function of these modifications and whether they are subject to regulation remains poorly understood. Thus, an outstanding question is whether individual pseudouridine modifications influence the ability of the ribosome to translate the transcriptome and more importantly whether the pattern of Ψ modifications on rRNA is differentially regulated. To this end we sought to determine the landscape of H/ACA snoRNA expression during the earliest cellular responses to oncogenic insult such as DNA damage. Unexpectedly, upon profiling H/ACA small RNAs in primary human fibroblasts, we observed coordinated regulation of specific subsets of H/ACA snoRNAs guiding modifications within similar regions of rRNA following DNA damage. The observed coordinated regulation in H/ACA snoRNA expression is functionally important as we observed a corresponding change in site-specific rRNA Ψ modifications within specific regions of the ribosome. Furthermore, we uncovered that loss of function of one snoRNA, SNORA24, and inhibition of its target rRNA Ψ modifications alters the translation of mRNAs implicated in lipid metabolism both in vitro and in vivo to maintain senescence, a stress response that acts as a critical barrier against cellular transformation. Rewired lipid metabolism results in increased lipid synthesis allowing for bypass of senescence in response to DNA damage in primary human fibroblasts and upon activation of oncogenic N-RasV12 in mouse liver. We further probed whether increased lipid synthesis upon loss of SNORA24 contributes to cellular transformation and tumor development. Strikingly, we observe that loss of function of SNORA24 cooperates with oncogenic N-RasV12 to develop hepatocellular carcinoma with significant accumulation of lipid droplets. These exciting findings provide the first evidence that the pattern of RNA base modifications within the ribosome are dynamically regulated in response to oncogenic insult and suggests a new layer of ribosome-mediated control in safeguarding the genome against cellular transformation.

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