Fan Wenjun, Liu Hester, Stachelek Gregory C, Begum Asma, Davis Catherine E, Dorado Tony E, Ernst Glen, Reinhold William C, Ozbek Busra, Zheng Qizhi, De Marzo Angelo M, Rajeshkumar N V, Barrow James C, Laiho Marikki
Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Lieber Institute for Brain Development, Baltimore, MD 21205, USA.
Cell Chem Biol. 2025 Jul 17;32(7):908-925.e9. doi: 10.1016/j.chembiol.2025.05.012. Epub 2025 Jun 18.
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.
核糖体生物合成是通过抑制RNA聚合酶I（Pol I）转录来靶向的癌症脆弱点。我们开发了特异性Pol I抑制剂，其可激活核糖体毒性应激途径以揭示敏感性驱动因素。整合来自大型癌细胞系的多组学和药物反应数据，我们发现RPL22移码突变赋予Pol I抑制剂敏感性。从机制上讲，RPL22直接与28S rRNA和mRNA剪接接头相互作用，作为剪接调节因子发挥作用。28S rRNA隔离加剧的RPL22缺陷促进其旁系同源物RPL22L1和p53负调节因子MDM4的剪接。rRNA合成的化学和基因抑制广泛重塑控制数百个靶点的mRNA剪接。值得注意的是，Pol I抑制可逆转RPL22依赖性可变剪接，揭示了一种非经典的核糖体毒性应激引发的肿瘤抑制途径。本研究揭示了一种由核糖体蛋白RPL22协调的将rRNA合成活性与剪接联系起来的强大机制。
