新的FANCM关联蛋白复合物FMAP150-FMAP160调控FANCM修复停滞复制叉的作用及机制

基因组不稳定性是细胞癌变的重要因素。DNA复制叉停滞是引发基因组不稳定性的主要来源。DNA损伤修复蛋白FANCM对修复停滞复制叉至关重要，但机制尚不清楚。我们前期发现一个新的FANCM关联蛋白复合物（FMAP150-FMAP160），揭示它是FANCM募集到停滞复制叉位点所必需的，且与FANCM一起作用来抵抗DNA复制压力。因此，本项目拟首先明确FMAP150-FMAP160复合物与FANCM互作的结构域；进而研究这一复合物在激活范可尼贫血DNA修复通路、促进复制跨越DNA链间交联以及调控FANCM功能的作用及机制；最后通过重组蛋白生化分析，明确FMAP150-FMAP160复合物对FANCM重启停滞复制叉活性的影响。本研究将揭示FANCM与FMAP150-FMAP160复合物构成一种保护DNA复制叉的新型蛋白轴。这不仅对基因组稳定性维持机制的深入阐明，还可为癌症治疗提供新思路和新靶标。

Genomic instability is an important factor for cell carcinogenesis. The stalled replication forks are the major source of genomic instability. FANCM, a DNA damage repair protein, plays a crucial role in the repair of stalled replication forks，but the underlying mechanism remains unclear. We have recently identified a novel FANCM-associated complex that consists of FMAP150 and FMAP160. We have demonstrated that FMAP150-FMAP160 complex is required for the recruitment of FANCM to stalled replication forks and works together with FANCM in the cellular resistance to DNA replication stress. In this proposal, we will first determine the interacting domains between FMAP150-FMAP160 complex and FANCM. We will then investigate the roles and mechanisms of action of FMAP150-FMAP160 complex in activating the Fanconi anemia DNA repair pathway, in promoting the replication traverse of DNA interstrand crosslinks and in regulating the function of FANCM. Finally, we will use biochemical assays with the recombinant proteins to determine the effect of FMAP150-FMAP160 complex on restarting the stalled replication forks by FANCM. The results from our studies will reveal that FMAP150-FMAP160 complex and FANCM constitute a novel protein axis for protection of replication forks, which will not only further elucidate the mechanism of maintaining genomic stability, but also provide new insights and targets for cancer treatment.