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

Cell Rep. 2019 Feb 26;26(9):2316-2328.e6. doi: 10.1016/j.celrep.2019.02.001.


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.

Keywords: DNA damage; RNA; genomic integrity; hematopoietic stem cells; protein arginine methyltransferase 5; proteostasis; splicing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Line
  • DNA Damage
  • DNA Repair
  • Genome
  • Hematopoietic Stem Cells / enzymology*
  • Hematopoietic Stem Cells / metabolism
  • Mice
  • Protein Biosynthesis
  • Protein-Arginine N-Methyltransferases / genetics
  • Protein-Arginine N-Methyltransferases / metabolism
  • Protein-Arginine N-Methyltransferases / physiology*
  • Proteostasis*
  • RNA Splicing*
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Suppressor Protein p53 / metabolism


  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • Prmt5 protein, mouse
  • Protein-Arginine N-Methyltransferases
  • mTOR protein, mouse
  • TOR Serine-Threonine Kinases