进展期胃癌预后不佳，申请人结合生物信息学分析和前期数据，发现DNA损伤修复蛋白MUS81是胃癌潜在治疗靶点。进一步研究发现MUS81通过降解R-loop促进胃癌细胞同源重组（HR）修复，质谱分析及相关实验结果提示MUS81能够结合解旋酶BLM并抑制其泛素化。鉴于BLM蛋白能够直接识别并降解细胞内R-loop，申请人推测MUS81通过结合BLM抑制其泛素化，降解细胞内R-loop并启动DSBs末端剪切，进而促进胃癌细胞HR修复。这一假设也为靶向MUS81增强胃癌细胞中PARP抑制剂抗肿瘤作用提供了理论基础。为验证以上假说，本课题拟进一步研究MUS81通过BLM降解R-loop促进胃癌细胞HR修复的分子机制，并明确靶向MUS81能否增强PARP抑制剂在胃癌细胞中的抗肿瘤作用。本项目的实施，有助于阐明MUS81调控胃癌细胞HR修复的分子机制，并为进展期胃癌临床治疗提供新的可能性

The prognosis of advanced gastric cancer is extremely poor, based on our preliminary data and bioinformatic analysis, we found that DNA damage repair-related protein MUS81 was a potential target for gastric cancer treatment. Further data indicated that targeting MUS81 suppressed HR repair via R-loop degradation. Results from MS analysis and related experiments revealed that MUS81 interacted and inhibited the ubiquitination of helicase BLM, which could directly recognize and degrade R-loop. Therefore, we assume that MUS81 binds BLM and inhibits its ubiquitination, to degrade the R-loop and initiate DSBs end resection, thus increasing HR repair ability. This also provides theoretical basis for targeting MUS81 to enhance the anticancer effect of PARP inhibitor in gastric cancer. To test our hypothesis, we will further study the mechanism by which MUS81 regulates BLM to promote HR repair via degrading R-loop, and determine whether MUS81 inhibition enhances the anticancer effect of PARP inhibitor in gastric cancer. This project will help to further understand the mechanism of MUS81 regulates HR repair and provides novel therapeutic strategy for advanced gastric cancer patients.