Tan DQ1, Li Y1, Yang C1, Li J1, Tan SH1, Chin DWL2, Nakamura-Ishizu A1, Yang H1, Suda T3.
1Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
2Department of Medicine, Huddinge, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden.
3Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
Protein arginine methyltransferase 5 (PRMT5) is essential for hematopoiesis, while PRMT5 inhibition remains a promising therapeutic strategy against various cancers. Here, we demonstrate that hematopoietic stem cell (HSC) quiescence and viability are severely perturbed upon PRMT5 depletion, which also increases HSC size, PI3K/AKT/mechanistic target of rapamycin (mTOR) pathway activity, and protein synthesis rate. We uncover a critical role for PRMT5 in maintaining HSC genomic integrity by modulating splicing of genes involved in DNA repair. We found that reducing PRMT5 activity upregulates exon skipping and intron retention events that impair gene expression. Genes across multiple DNA repair pathways are affected, several of which mediate interstrand crosslink repair and homologous recombination. Consequently, loss of PRMT5 activity leads to endogenous DNA damage that triggers p53 activation, induces apoptosis, and culminates in rapid HSC exhaustion, which is significantly delayed by p53 depletion. Collectively, these findings establish the importance of cell-intrinsic PRMT5 activity in HSCs.
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
DNA damage; RNA; genomic integrity; hematopoietic stem cells; protein arginine methyltransferase 5; proteostasis; splicing