Deletion of RBMX RGG/RG motif in Shashi-XLID syndrome leads to aberrant p53 activation and neuronal differentiation defects
Ting Cai,
Jessica K. Cinkornpumin,
Zhenbao Yu,
Oscar D. Villarreal,
William A. Pastor,
Stéphane Richard
Affiliations
Ting Cai
Segal Cancer Center, Lady Davis Institute for Medical Research and Gerald Bronfman Department of Oncology, and Departments of Biochemistry, Human Genetics, and Medicine, McGill University, Montréal, QC H3T 1E2, Canada; Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada
Jessica K. Cinkornpumin
Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada; Rosalind & Morris Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada
Zhenbao Yu
Segal Cancer Center, Lady Davis Institute for Medical Research and Gerald Bronfman Department of Oncology, and Departments of Biochemistry, Human Genetics, and Medicine, McGill University, Montréal, QC H3T 1E2, Canada
Oscar D. Villarreal
Segal Cancer Center, Lady Davis Institute for Medical Research and Gerald Bronfman Department of Oncology, and Departments of Biochemistry, Human Genetics, and Medicine, McGill University, Montréal, QC H3T 1E2, Canada
William A. Pastor
Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada; Rosalind & Morris Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada
Stéphane Richard
Segal Cancer Center, Lady Davis Institute for Medical Research and Gerald Bronfman Department of Oncology, and Departments of Biochemistry, Human Genetics, and Medicine, McGill University, Montréal, QC H3T 1E2, Canada; Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada; Corresponding author
Summary: RNA-binding proteins play important roles in X-linked intellectual disability (XLID). In this study, we investigate the contribution of the XLID-associated RBMX in neuronal differentiation. We show that RBMX-depleted cells exhibit aberrant activation of the p53 pathway. Moreover, we identify that the RBMX RGG/RG motif is methylated by protein arginine methyltransferase 5 (PRMT5), and this regulates assembly with the SRSF1 splicing factor into higher-order complexes. Depletion of RBMX or disruption of the RBMX/SRSF1 complex in PRMT5-depleted cells reduces SRSF1 binding to the MDM4 precursor (pre-)mRNA, leading to exon 6 exclusion and lower MDM4 protein levels. Transcriptomic analysis of isogenic Shashi-XLID human-induced pluripotent stem cells (hiPSCs) generated using CRISPR-Cas9 reveals a dysregulation of MDM4 splicing and aberrant p53 upregulation. Shashi-XLID neural progenitor cells (NPCs) display differentiation and morphological abnormalities accompanied with excessive apoptosis. Our findings identify RBMX as a regulator of SRSF1 and the p53 pathway, suggesting that the loss of function of the RBMX RGG/RG motif is the cause of Shashi-XLID syndrome.
