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
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.
