The ribosomal protein L22 binds the MDM4 pre-mRNA and promotes exon skipping to activate p53 upon nucleolar stress

The tumor suppressor p53, along with its antagonists MDM2 and MDM4, represents a central integrator of stress signaling. While DNA damage is the most widely explored trigger of a p53 response, stress arising from dysbalanced assembly of ribosomes in nucleoli is also linked to p53 induction. Deletions of the gene encoding the ribosomal protein L22 (RPL22; eL22) correlate with the presence of full-length MDM4 mRNA in human cancer, but the mechanistic basis for this phenomenon was hitherto unknown. Here we show that L22, under conditions of ribosomal and nucleolar stress, promotes the skipping of exon 6 within the MDM4 pre-mRNA. Upon L22 depletion, more full-length MDM4 is maintained, independent of treatment with nucleolar stressors, leading to diminished p53 activity and enhanced cellular proliferation. Mechanistically, L22 binds to specific RNA elements within intron 6 of MDM4 that correspond to a stem-loop consensus, leading to the skipping of exon 6. This intronic RNA overlaps with the region responsible for splice regulation by ZMAT3. Targeted deletion of these intronic elements largely abolishes L22-mediated exon skipping and re-enables cell proliferation, despite nucleolar stressors such as 5-fluorouracil. L22 also governs alternative splicing of the L22L1 (RPL22L1) and UBAP2L mRNAs. Thus, L22 serves as a signaling intermediate that integrates different layers of gene expression. Defects in ribosome synthesis lead to specific alternative splicing, ultimately triggering p53-mediated transcription and arresting cell proliferation.