MRE11的UFM1修饰调控复制叉稳定性的作用机制

复制压力诱导的复制叉不稳定是基因组不稳定和肿瘤发生及耐药的重要因素，MRE11对复制叉的降解是BRCA1/2缺陷肿瘤细胞对PARP1抑制剂敏感的关键因素。我之前发现MRE11的UFM1修饰调控DSB损伤应答，我的预实验首次发现UFL1缺失和MRE11的UFM1修饰缺陷都显著降低复制叉的降解，可见MRE11的UFM1修饰促进复制叉的稳定性，因此我提出假设：UFL1通过MRE11的UFM1修饰调控复制叉稳定性，从而影响基因组的稳定和肿瘤的发生及耐药。通过对复制压力信号转导、复制叉的降解和重启、基因组稳定性、肿瘤细胞成瘤能力和耐药性等方面的研究，本项目将阐明MRE11的UFM1修饰对复制叉稳定性的调控机制，以及对BRCA1/2缺陷肿瘤细胞基因组稳定性和耐药性的影响。这不仅将丰富和完善复制压力应答网络，也为BRCA1/2缺陷乳腺癌和卵巢癌治疗提供新的策略和思路。

Replication fork instability induced by replication stress leads to genomic instability, tumorigenesis and drug-resistance. The degradation of replication fork by the nuclease MRE11 is a key factor in the sensitization of BRCA1/2-negative tumor to PARP1 inhibitors. My previous work demonstrated for the first time that MRE11 UFMylation modulates DSBs response, and my preliminary experiments showed that both UFL1 depletion and UFMylation-defective MRE11 significantly reduced the degradation of stalled replication forks, indicating that MRE11 UFMylation promotes replication forks stability. Therefore, I hypothesize that, via MRE11 UFMylation, UFL1 modulates replication forks stability, thus affecting genomic integrity, tumorigenesis and drug-resistance. This proposal will explore replication stress signal transduction, the replication fork degradation and restart, and genomic integrity, as well as cancer cell’s tumorigenesis and drug-resistance. Accomplishment of this proposal will elucidate the regulatory mechanism of MRE11 UFMylation on the stability of replication forks, and its effects on genomic integrity and drug resistance of BRCA1/2-negative cancer cells. This will elaborate the replication stress response network, providing potential novel targets and strategies for the therapy of BRCA1/2-negative breast and ovarian cancer.