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RPL22 is a tumor suppressor in MSI-high cancers and a splicing regulator of MDM4.
Weinstein, Hannah N W; Hu, Kevin; Fish, Lisa; Chen, Yih-An; Allegakoen, Paul; Pham, Julia H; Hui, Keliana S F; Chang, Chih-Hao; Tutar, Meltem; Benitez-Rivera, Lorena; Baco, Maria B; Song, Hanbing; Giacomelli, Andrew O; Vazquez, Francisca; Ghandi, Mahmoud; Goodarzi, Hani; Huang, Franklin W.
Afiliação
  • Weinstein HNW; 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.
  • Hu K; 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.
  • Fish L; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
  • Chen YA; 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.
  • Allegakoen P; 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.
  • Pham JH; 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.
  • Hui KSF; 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.
  • Chang CH; 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.
  • Tutar M; 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.
  • Benitez-Rivera L; 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.
  • Baco MB; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Song H; 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.
  • Giacomelli AO; Tumor Immunotherapy Program, Princess Margaret Cancer Center, Toronto, ON, Canada.
  • Vazquez F; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Ghandi M; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Goodarzi H; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
  • Huang FW; 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; Chan Zuckerberg Biohub San Francisco, San Francisco,
Cell Rep ; 43(8): 114622, 2024 Aug 27.
Article em En | MEDLINE | ID: mdl-39146182
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Ribossômicas / Proteínas de Ciclo Celular Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Ribossômicas / Proteínas de Ciclo Celular Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article