PRMT5 regulates the homologous recombination DNA repair pathway by controlling the alternative splicing of key epigenetic factors

We found that PRMT5 deletion or inhibition impairs homologous recombination (HR) DNA repair, leading to DNA damage accumulation, p53 activation, cell cycle arrest and cell death through missplicing of KAT5. We show that PRMT5 inhibitors and PARP inhibitors have synergistic effects on human acute leukemia cell lines, demonstrating the advantages of combining targeted epigenetic and non-epigenetic inhibitors. RNA from sorted E14.5 Ter119-/+ mouse fetal liver cells from Vav-cre;PRMT5fl/fl (KO) and PRMT5fl/fl (WT) were subjected to high-throughput RNA sequencing. RNA from sorted LK cells from Mx1-cre;PRMT5fl/fl (KO) and PRMT5fl/fl (WT) collected 7 days after poly(I:C) injections were subjected to high-throughput RNA sequencing.我们发现，PRMT5的缺失或抑制可通过KAT5的异常剪接损伤同源重组（HR）DNA修复通路，进而引发DNA损伤累积、p53激活、细胞周期阻滞及细胞死亡。我们证实，PRMT5抑制剂与PARP抑制剂对人急性白血病细胞系具有协同效应，凸显了表观遗传靶向抑制剂与非表观遗传靶向抑制剂联合应用的优势。我们对两组样本的RNA进行了高通量RNA测序：第一组为来自Vav-cre;PRMT5fl/fl（基因敲除组，KO）与PRMT5fl/fl（野生型组，WT）的分选E14.5天Ter119-/+小鼠胎肝细胞提取的RNA；第二组为经poly(I:C)（聚肌苷酸-聚胞苷酸）注射7天后分选获得的Mx1-cre;PRMT5fl/fl（KO）与PRMT5fl/fl（WT）小鼠LK细胞提取的RNA。