ABSTRACT
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.
Subject(s)
Cell Cycle Proteins , Ribosomal Proteins , Humans , Ribosomal Proteins/metabolism , Ribosomal Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Cycle Proteins/genetics , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins/genetics , Neoplasms/genetics , Neoplasms/pathology , Neoplasms/metabolism , Cell Line, Tumor , Alternative Splicing/genetics , Cell Proliferation/genetics , Animals , Exons/genetics , Mice , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/genetics , Nuclear Proteins/metabolism , Nuclear Proteins/genetics , Gene Expression Regulation, Neoplastic , Piperazines/pharmacology , Imidazoles/pharmacologyABSTRACT
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, cell proliferation, and augments resistance to the MDM inhibitor Nutlin-3a. RPL22 represses 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.