PRMT5 Modulates Splicing for Genome Integrity and Preserves Proteostasis of Hematopoietic Stem Cells

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. [Display omitted] •HSC size and protein synthesis rate increase upon depletion of PRMT5 activity•PRMT5 depletion leads to AKT/mTOR activation, which partly contributes to HSC loss•PRMT5 activity is required for splicing of DNA repair genes in multiple cell types•PRMT5 KO or inhibition causes oxidative DNA damage that triggers p53-induced apoptosis Tan et al. demonstrate that depletion of PRMT5 activity in hematopoietic stem cells (HSCs) perturbs protein homeostasis, and they uncover a conserved role for PRMT5 in maintaining genomic integrity by modulating splicing of DNA repair genes. These findings underscore the need to maintain an adequate level of PRMT5 activity in HSCs.