Division of Hematology/Oncology, Department of Medicine, Helen Diller Family Comprehensive Cancer Center, Bakar Computational Health Sciences Institute, Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
Cell Rep. 2024 Aug 27;43(8):114622. doi: 10.1016/j.celrep.2024.114622. Epub 2024 Aug 14.
Microsatellite instability-high (MSI-H) tumors are malignant tumors that, despite harboring a high mutational burden, often have intact TP53. One of the most frequent mutations in MSI-H tumors is a frameshift mutation in RPL22, a ribosomal protein. Here, we identified RPL22 as a modulator of MDM4 splicing through an alternative splicing switch in exon 6. RPL22 loss increases MDM4 exon 6 inclusion and cell proliferation and augments resistance to the MDM inhibitor Nutlin-3a. RPL22 represses the expression of its paralog, RPL22L1, by mediating the splicing of a cryptic exon corresponding to a truncated transcript. Therefore, damaging mutations in RPL22 drive oncogenic MDM4 induction and reveal a common splicing circuit in MSI-H tumors that may inform therapeutic targeting of the MDM4-p53 axis and oncogenic RPL22L1 induction.
微卫星不稳定性高（MSI-H）肿瘤是恶性肿瘤，尽管存在高突变负担，但通常具有完整的 TP53。MSI-H 肿瘤中最常见的突变之一是核糖体蛋白 RPL22 的移码突变。在这里，我们通过 6 号外显子中的选择性剪接开关鉴定 RPL22 是 MDM4 剪接的调节剂。RPL22 的缺失增加了 MDM4 外显子 6 的包含和细胞增殖，并增强了对 MDM 抑制剂 Nutlin-3a 的耐药性。RPL22 通过介导与截断转录本相对应的隐藏外显子的剪接来抑制其同源物 RPL22L1 的表达。因此，RPL22 的破坏性突变驱动致癌性 MDM4 的诱导，并揭示了 MSI-H 肿瘤中常见的剪接回路，这可能为 MDM4-p53 轴的治疗靶向和致癌性 RPL22L1 诱导提供信息。
