PRMT5 Regulates DNA Repair by Controlling the Alternative Splicing of Histone-Modifying Enzymes

Pierre Jacques Hamard, Gabriel E. Santiago, Fan Liu, Daniel L. Karl, Concepcion Martinez, Na Man, Adnan K. Mookhtiar, Stephanie Duffort, Sarah Greenblatt, Ramiro E Verdun, Stephen D Nimer

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Protein arginine methyltransferase 5 (PRMT5) is overexpressed in many cancer types and is a promising therapeutic target for several of them, including leukemia and lymphoma. However, we and others have reported that PRMT5 is essential for normal physiology. This dependence may become dose limiting in a therapeutic setting, warranting the search for combinatorial approaches. Here, we report that PRMT5 depletion or inhibition impairs homologous recombination (HR) DNA repair, leading to DNA-damage accumulation, p53 activation, cell-cycle arrest, and cell death. PRMT5 symmetrically dimethylates histone and non-histone substrates, including several components of the RNA splicing machinery. We find that PRMT5 depletion or inhibition induces aberrant splicing of the multifunctional histone-modifying and DNA-repair factor TIP60/KAT5, which selectively affects its lysine acetyltransferase activity and leads to impaired HR. As HR deficiency sensitizes cells to PARP inhibitors, we demonstrate here that PRMT5 and PARP inhibitors have synergistic effects on acute myeloid leukemia cells. Hamard et al. show that PRMT5 regulates DNA-repair efficiency in hematopoietic cells by controlling the alternative splicing of key histone modifying and DNA-repair proteins, including TIP60. PRMT5 depletion or inhibition leads to a defect in DNA-repair pathway choice, which may be exploited therapeutically to target acute leukemia cells.

Original languageEnglish (US)
Pages (from-to)2643-2657
Number of pages15
JournalCell Reports
Volume24
Issue number10
DOIs
StatePublished - Sep 4 2018

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Keywords

  • 53BP1
  • acute myeloid leukemia
  • alternative splicing
  • DNA damage and repair
  • hematopoiesis
  • histone post-translational modifications acetylation
  • homologous recombination
  • methylation
  • PARP inhibitor
  • PRMT5
  • PRMT5 inhibitor
  • Tip60/KAT5

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Hamard, P. J., Santiago, G. E., Liu, F., Karl, D. L., Martinez, C., Man, N., Mookhtiar, A. K., Duffort, S., Greenblatt, S., Verdun, R. E., & Nimer, S. D. (2018). PRMT5 Regulates DNA Repair by Controlling the Alternative Splicing of Histone-Modifying Enzymes. Cell Reports, 24(10), 2643-2657. https://doi.org/10.1016/j.celrep.2018.08.002