Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Medicine, Division of Hematology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Cell Rep. 2018 Sep 4;24(10):2643-2657. doi: 10.1016/j.celrep.2018.08.002.
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.
蛋白质精氨酸甲基转移酶 5（PRMT5）在许多癌症类型中过表达，是许多癌症（包括白血病和淋巴瘤）的有前途的治疗靶点。然而，我们和其他人已经报道 PRMT5 对正常生理是必需的。这种依赖性在治疗环境中可能成为剂量限制因素，需要寻找联合治疗方法。在这里，我们报告 PRMT5 的耗竭或抑制会损害同源重组（HR）DNA 修复，导致 DNA 损伤积累、p53 激活、细胞周期停滞和细胞死亡。PRMT5 对称地甲基化组蛋白和非组蛋白底物，包括 RNA 剪接机制的几个成分。我们发现 PRMT5 的耗竭或抑制会诱导多功能组蛋白修饰和 DNA 修复因子 TIP60/KAT5 的异常剪接，这会选择性地影响其赖氨酸乙酰转移酶活性，并导致 HR 受损。由于 HR 缺陷使细胞对 PARP 抑制剂敏感，我们在这里证明 PRMT5 和 PARP 抑制剂对急性髓系白血病细胞具有协同作用。
