RSL24D1 links ribosome biogenesis to p53 activation in melanoma

Abstract Melanoma cells exhibit elevated translation activity and rely on intact ribosomes to sustain their high protein synthesis demand. To support this process, efficient ribosome biogenesis is essential. RSL24D1 is a ribosome biogenesis factor required for late-stage maturation of the 60S ribosomal subunit. By ensuring correct ribosomal assembly, RSL24D1 supports global protein translation and maintains cellular homeostasis. Transcript and protein analyses revealed that RSL24D1 is upregulated in melanoma cells compared to normal human epidermal melanocytes. This overexpression correlates with reduced patient survival, suggesting an oncogenic role. Reduction of RSL24D1 expression impaired protein synthesis, decreased cell growth and resulted in the accumulation of unincorporated ribosomal proteins RPL5 and RPL11, which form the 5S RNP complex and inhibit the binding of MDM2 to p53. This inhibition stabilised p53 and activated downstream targets, including CDKN1A , resulting in G1 phase arrest and a senescence-like phenotype. These findings identify RSL24D1 as a critical component linking ribosome biogenesis to the p53 stress response. Targeting RSL24D1 creates a translational bottleneck, suppressing cell growth in p53 wild-type and p53-mutant cancer cells, highlighting it as a potential therapeutic target.