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

Autor:	Jansen J; Department of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany., Bohnsack KE; Department of Molecular Biology, University Medical Center Göttingen, Humboldtallee 23, 37073 Göttingen, Germany., Böhlken-Fascher S; Department of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany., Bohnsack MT; Department of Molecular Biology, University Medical Center Göttingen, Humboldtallee 23, 37073 Göttingen, Germany., Dobbelstein M; Department of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany. Electronic address: mdobbel@uni-goettingen.de.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2024 Aug 27; Vol. 43 (8), pp. 114610. Date of Electronic Publication: 2024 Aug 07.
DOI:	10.1016/j.celrep.2024.114610
Abstrakt:	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.)
Databáze:	MEDLINE
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