PRMT5 regulates the homologous recombination DNA repair pathway by controlling the alternative splicing of key epigenetic factors. 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. Overall design: 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缺失或抑制会损伤同源重组（homologous recombination，HR）DNA修复，通过KAT5的错剪接引发DNA损伤蓄积、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（poly(ADP-ribose) polymerase inhibitor）对人急性白血病细胞系具有协同作用，印证了靶向表观遗传抑制剂与非表观遗传抑制剂联合使用的优势。
实验整体设计：
提取Vav-cre;PRMT5fl/fl（KO组，knockout）与PRMT5fl/fl（WT组，wild type）小鼠E14.5胎肝中分选得到的Ter119-/+细胞的总RNA，对其进行高通量RNA测序；在经poly(I:C)（聚肌胞苷酸）注射7天后，提取Mx1-cre;PRMT5fl/fl（KO组，knockout）与PRMT5fl/fl（WT组，wild type）小鼠体内分选得到的LK细胞的总RNA，同样开展高通量RNA测序。