1. The ribosomal protein L22 binds the MDM4 pre-mRNA and promotes exon skipping to activate p53 upon nucleolar stress.
- Author
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Jansen J, Bohnsack KE, Böhlken-Fascher S, Bohnsack MT, and Dobbelstein M
- Subjects
- Humans, Cell Nucleolus metabolism, Cell Proliferation, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins genetics, Protein Binding, Cell Cycle Proteins metabolism, Cell Cycle Proteins genetics, Nuclear Proteins metabolism, Nuclear Proteins genetics, Ribosomes metabolism, Stress, Physiological genetics, RNA-Binding Proteins, Ribosomal Proteins metabolism, Ribosomal Proteins genetics, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Protein p53 genetics, Exons genetics, RNA Precursors metabolism, RNA Precursors genetics, Alternative Splicing genetics
- Abstract
The tumor suppressor p53 and its antagonists MDM2 and MDM4 integrate stress signaling. For instance, dysbalanced assembly of ribosomes in nucleoli induces p53. Here, we show that the ribosomal protein L22 (RPL22; eL22), under conditions of ribosomal and nucleolar stress, promotes the skipping of MDM4 exon 6. Upon L22 depletion, more full-length MDM4 is maintained, leading to diminished p53 activity and enhanced cellular proliferation. L22 binds to specific RNA elements within intron 6 of MDM4 that correspond to a stem-loop consensus, leading to exon 6 skipping. Targeted deletion of these intronic elements largely abolishes L22-mediated exon skipping and re-enables cell proliferation, despite nucleolar stress. 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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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