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

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

Cell Reports (Aug 2024)

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

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

Affiliations

Hannah N.W. Weinstein: 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
Kevin Hu: 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
Lisa Fish: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
Yih-An Chen: 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
Paul Allegakoen: 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
Julia H. Pham: 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
Keliana S.F. Hui: 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
Chih-Hao Chang: 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
Meltem Tutar: 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
Lorena Benitez-Rivera: 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
Maria B. Baco: Broad Institute of MIT and Harvard, Cambridge, MA, USA
Hanbing Song: 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
Andrew O. Giacomelli: Tumor Immunotherapy Program, Princess Margaret Cancer Center, Toronto, ON, Canada
Francisca Vazquez: Broad Institute of MIT and Harvard, Cambridge, MA, USA
Mahmoud Ghandi: Broad Institute of MIT and Harvard, Cambridge, MA, USA
Hani Goodarzi: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
Franklin W. Huang: 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, CA, USA; San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA; Corresponding author

Journal volume & issue: Vol. 43, no. 8
p. 114622

Abstract

Read online

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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

About the journal

Abstract

Keywords