RPL22 is a tumor suppressor in MSI-high cancers and a key splicing regulator of MDM4

Weinstein, H. N. W.; Hu, K.; Fish, L.; Chen, Y.-A.; Allegakoen, P.; Hui, K. S. F.; Pham, J. H.; Baco, M. B.; Song, H.; Giacomelli, A. O.; Vazquez, F.; Ghandi, M.; Goodarzi, H.; Huang, F. W.

doi:10.1101/2023.12.10.570873

bioRxiv · 10.1101/2023.12.10.570873

RPL22 is a tumor suppressor in MSI-high cancers and a key splicing regulator of MDM4

Weinstein, H. N. W.·Hu, K.·Fish, L.·Chen, Y.-A.·Allegakoen, P.·Hui, K. S. F.·Pham, J. H.·Baco, M. B.·Song, H.·Giacomelli, A. O.·Vazquez, F.·Ghandi, M.·Goodarzi, H.·Huang, F. W.

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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, 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.

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Weinstein, H. N. W., Hu, K., Fish, L., Chen, Y.-A., Allegakoen, P., Hui, K. S. F., Pham, J. H., Baco, M. B., Song, H., Giacomelli, A. O., Vazquez, F., Ghandi, M., Goodarzi, H., Huang, F. W.. 2023-12-10. RPL22 is a tumor suppressor in MSI-high cancers and a key splicing regulator of MDM4. https://doi.org/10.1101/2023.12.10.570873

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