2. Academic Validation
  3. Ribosomal RNA transcription regulates splicing through ribosomal protein RPL22

Ribosomal RNA transcription regulates splicing through ribosomal protein RPL22

  • Cell Chem Biol. 2025 Jul 17;32(7):908-925.e9. doi: 10.1016/j.chembiol.2025.05.012.
Wenjun Fan 1,  Hester Liu 1,  Gregory C Stachelek 1,  Asma Begum 1,  Catherine E Davis 1,  Tony E Dorado 2,  Glen Ernst 2,  William C Reinhold 3,  Busra Ozbek 4,  Qizhi Zheng 4,  Angelo M De Marzo 5,  N V Rajeshkumar 6,  James C Barrow 7,  Marikki Laiho 8
Affiliations

Affiliations

  • 1 Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • 2 Lieber Institute for Brain Development, Baltimore, MD 21205, USA.
  • 3 Developmental Therapeutics Branch, NCI, NIH, Bethesda, MD 20892, USA.
  • 4 Department of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • 5 Department of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • 6 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • 7 Lieber Institute for Brain Development, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • 8 Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland. Electronic address: mlaiho1@jhmi.edu.
PMID: 40553690 DOI: 10.1016/j.chembiol.2025.05.012
Abstract

Ribosome biosynthesis is a Cancer vulnerability targeted by inhibiting RNA polymerase I (Pol I) transcription. We developed specific Pol I inhibitors that activate a ribotoxic stress pathway to uncover drivers of sensitivity. Integrating multi-omics and drug response data from a large Cancer cell panel, we found that RPL22 frameshift mutations confer Pol I inhibitor sensitivity. Mechanistically, RPL22 interacts directly with 28S rRNA and mRNA splice junctions, acting as a splicing regulator. RPL22 deficiency, intensified by 28S rRNA sequestration, promotes splicing of its paralog RPL22L1 and the p53 negative regulator MDM4. Both chemical and genetic inhibition of rRNA synthesis broadly remodel mRNA splicing controlling hundreds of targets. Notably, RPL22-dependent alternative splicing is reversed by Pol I inhibition, revealing a non-canonical ribotoxic stress-initiated tumor suppressive pathway. This study uncovers a robust mechanism linking rRNA synthesis activity to splicing, coordinated by the ribosomal protein RPL22.

Keywords

MDM4; RPL22; RPL22L1; cancer; nucleolus; rRNA synthesis; ribosome biogenesis; small-molecule; splicing; therapeutics.

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