Department of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany.
Department of Molecular Biology, University Medical Center Göttingen, Humboldtallee 23, 37073 Göttingen, Germany.
Cell Rep. 2024 Aug 27;43(8):114610. doi: 10.1016/j.celrep.2024.114610. Epub 2024 Aug 7.
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.
肿瘤抑制因子 p53 及其拮抗剂 MDM2 和 MDM4 整合应激信号。例如，核仁中核糖体的不平衡组装会诱导 p53。在这里，我们表明核糖体蛋白 L22（RPL22；eL22）在核糖体和核仁应激条件下促进 MDM4 外显子 6 的跳过。在 L22 耗尽的情况下，更多的全长 MDM4 得以维持，导致 p53 活性降低和细胞增殖增强。L22 与 MDM4 内含子 6 内的特定 RNA 元件结合，这些元件对应茎环保守序列，导致外显子 6 跳过。这些内含子元件的靶向缺失在很大程度上消除了 L22 介导的外显子跳跃，并重新激活了细胞增殖，尽管存在核仁应激。L22 还调控 L22L1（RPL22L1）和 UBAP2L mRNA 的可变剪接。因此，L22 作为一种信号中间物，整合了不同层次的基因表达。核糖体合成缺陷会导致特定的可变剪接，最终触发 p53 介导的转录并阻止细胞增殖。
