| Autor: |
Hannah N.W. Weinstein, Kevin Hu, Lisa Fish, Yih-An Chen, Paul Allegakoen, Julia H. Pham, Keliana S.F. Hui, Chih-Hao Chang, Meltem Tutar, Lorena Benitez-Rivera, Maria B. Baco, Hanbing Song, Andrew O. Giacomelli, Francisca Vazquez, Mahmoud Ghandi, Hani Goodarzi, Franklin W. Huang |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
Cell Reports, Vol 43, Iss 8, Pp 114622- (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2211-1247 |
| DOI: |
10.1016/j.celrep.2024.114622 |
| Popis: |
Summary: 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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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