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.
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•PRMT5 depletion leads to increased DNA damage in hematopoietic cells•PRMT5 deficiency affects splicing of the key DNA-repair pathway component TIP60•PRMT5-deficient hematopoietic cells have impaired homologous recombination DNA repair•These defects may be exploited therapeutically by combining PRMT5 and PARP inhibitors
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.
