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

Cell Reports
Darren Qiancheng TanToshio Suda

Abstract

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.

Citations

Sep 29, 2020·Scientific Reports·Antja-Voy HartleyTao Lu
Jun 20, 2020·Scientific Reports·Ann-Kathrin SchnormeierMax Koeppel
May 19, 2019·Cellular and Molecular Life Sciences : CMLS·Benjamin M Lorton, David Shechter
Jul 28, 2020·Cell Death & Disease·Wojciech BarczakNicholas B La Thangue
Jul 25, 2019·Genes, Chromosomes & Cancer·Justin Taylor, Stanley C Lee
Jul 28, 2019·Nature Reviews. Molecular Cell Biology·Ernesto Guccione, Stéphane Richard
Dec 11, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Renato Ferreira de FreitasMatthieu Schapira
Jan 9, 2021·The Journal of Pathology. Clinical Research·Shuyu MeiTingguo Zhang
Jan 15, 2021·Nucleic Acids Research·Steffen ErkelenzMirka Uhlirova
Feb 12, 2020·Genes & Diseases·Fen Zhu, Lixin Rui
Jan 21, 2021·Cellular Oncology (Dordrecht)·Yuanyang Yuan, Hong Nie
Feb 16, 2021·Stem Cell Reviews and Reports·Hélia FernandesEugénia Carvalho
Mar 27, 2021·Epigenomes·Tanner WrightMark T Bedford
Apr 16, 2021·Cancer Gene Therapy·Elena BeketovaChang-Deng Hu
May 12, 2021·Current Opinion in Hematology·Sisi Chen, Omar Abdel-Wahab
Jun 22, 2021·PLoS Genetics·Aurélie QuillienLaurence Vandel
Jul 12, 2021·Topics in Companion Animal Medicine·C Guillermo CoutoCorie Drake
Jul 22, 2020·Developmental Cell·Ayako Nakamura-IshizuToshio Suda
Sep 14, 2021·Frontiers in Cell and Developmental Biology·Zhenzhen LiangXiaodong Liu
Dec 17, 2021·The Journal of Immunology : Official Journal of the American Association of Immunologists·Yingxia ZhengLisong Shen

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