FAK-OTUD4-POLQ信号轴调控微同源介导末端连接修复（MMEJ）及肿瘤耐药的分子机制研究

微同源介导的末端连接修复(MMEJ)是一种选择性非同源末端连接修复，是除了同源重组修复（HR）及非同源末端连接修复（NHEJ）以外，主要的DNA双链修复方式。有报道，HR缺陷型肿瘤细胞可以利用MMEJ替代HR，修复PARP抑制剂介导的DNA损伤，进而引起这类肿瘤对PARP抑制剂的耐受。POLQ是一种DNA聚合酶，是MMEJ关键调控因子。对于POLQ如何受去泛素化修饰调控，尚无报道。本项目前期发现OTUD4去泛素化POLQ，酪氨酸激酶FAK磷酸化OTUD4并正向调控POLQ蛋白水平。我们拟研究FAK-OTUD4-POLQ信号轴调控MMEJ分子机制。TCGA数据显示FAK在28%的卵巢癌中拷贝数增多，包括部分HR缺陷型肿瘤。我们将利用细胞及小鼠模型，研究FAK-OTUD4-POLQ信号轴是否介导PARP抑制剂耐受，并探索FAK抑制剂联合PARP抑制剂杀伤HR缺陷型卵巢癌的可行性。

Microhomology-mediated end joining (MMEJ), is one kind of alternative nonhomologous end-joining (Alt-NHEJ), which is one of the pathways for repairing double-strand breaks in DNA besides Homologous Recombination (HR) and Non-homologous end joining (NHEJ). Previous report showed that HR deficient cancers utilized MMEJ in stead of HR to repair PARP inhibitor mediated DNA damage, which may cause chemoresistance in these caners. POLQ is one kind of DNA polymerases and play an important role in MMEJ. However, how POLQ is regulated by protein post-translational modification, especially deubiquitination is unknown. Our preliminary data showed that OTUD4 deubiquitinated POLQ. Furthermore, FAK phosphorylated OTUD4 and upregulated POLQ protein level. We will study the role of FAK-OTUD4-POLQ axis in regulation of MMEJ. TCGA data showed that FAK is amplificated in 28% ovarian cancer patients, part of them are HR deficient. We will study the role of FAK-OTUD4-POLQ axis in chemoresistance and further investigated the strategy by combining FAK inhibitor and PARP inhibitor in treating HR deficient ovarian cancer, which has developed chemoresistance for PARP inhibition.