THE ROLE OF PROTEIN ARGININE METHYLTRANSFERASE 5 IN HEMATOPOIESIS

Abstract

Protein arginine methyltransferase 5 (PRMT5) is essential for hematopoiesis, while PRMT5 inhibition remains a promising therapeutic strategy against various cancers. However, the requirement for PRMT5 in the hematopoietic stem cell (HSC) compartment remains unclear. Here, we demonstrate that HSC quiescence and viability are severely perturbed upon PRMT5 depletion; which also increases HSC size, PI3K/AKT/mTOR pathway activity, and protein synthesis rate. We further 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. Notably, 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 unresolved 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.