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

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.

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Publication Details

Journal
Cell Reports
Published
2024-08-01
DOI
https://doi.org/10.1016/j.celrep.2024.114622
Citations
18
Primary Topic
RNA Research and Splicing
Type
article
Field-Weighted Citation Impact
4.21

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article

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

Mahmoud Ghandi, Lisa Fish, Hanbing Song, H Weinstein et al.
18 citations
Cell Reports
RNA Research and Splicing
4.21
article

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

Mahmoud Ghandi, Lisa Fish, Hanbing Song, H Weinstein, Lorena Benitez-Rivera, Paul Allegakoen, Francisca Vázquez, Maria B. Baco, Andrew O. Giacomelli, Chih‐Hao Chang, Franklin W. Huang, Hani Goodarzi, Kevin Hu, Yih-An Chen, Meltem Tutar, Keliana S F Hui, Julia H Pham
article en
18 citations

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.

Cell ReportsVol. 43(8)
Broad Institute (US), University of California, San Francisco (US), Princess Margaret Cancer Centre (CA), UCSF Helen Diller Family Comprehensive Cancer Center (US)
U.S. Department of Veterans Affairs, Prostate Cancer Foundation, National Institutes of Health, University of California, San Francisco
Good health and well-being
Openalex Percentile: Top 5%
RNA Research and Splicing
4.21
DOIOpen Access PDFOpenAlex
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