HTATSF1调控基因组稳定性的分子机理研究

DNA损伤应答（DDR）协调着DNA复制、修复和细胞周期检查点控制，是基因组稳定性维持的重要手段。支架蛋白TOPBP1含有多个BRCT结构域，是DDR的关键调控因子之一，但是目前尚不清楚其如何参与DDR和同源重组（HR）修复。我们初步研究发现：染色质结合因子HTATSF1与TOPBP1相互作用，促进TOPBP1在损伤位点募集；HTATSF1缺失后细胞HR能力降低；HTATSF1在乳腺癌中高表达，敲低后使癌细胞对PARP抑制剂更敏感。据此，我们假说：DNA损伤时，TOPBP1通过与HTATSF1相互作用特异地在损伤位点募集、促进HR修复，最终赋予肿瘤细胞抵抗DNA损伤的能力。然而HTATSF1如何与TOPBP1结合、调控TOPBP1募集等科学问题还有待深入探索。以上问题的阐明，有助于我们理解DDR和基因组稳定性的调节机制，拓宽我们对HTATSF1功能的认识，为乳腺癌治疗提供潜在的靶点。

In response to genotoxic pressure from both endogenous and exogenous sources, cells have evolved a coordinated network of DNA damage response (DDR) to maintain the integrity of their genomes. The DDR process is a signal-transduction pathway that coordinates DNA replication, DNA repair, chromosome segregation, and cell-cycle checkpoint control. Unscheduled DDR may give rise to deleterious mutations that may prove lethal to the cell or induce aberrant cellular behaviour leading to the development of malignancies such as cancer. TOPBP1 (DNA topoisomerase 2-binding protein 1), a conserved multi-BRCT (BRCA1 C-terminal) domain scaffolding protein, acts as a key regulator of DDR. Yet, it is still unknown that how it is involved in DDR and repair of DNA double-strand breaks via homologous recombination. In this study, we initially found that TOPBP1 is physically associated with chromatin binding protein HTATSF1 and the recruitment of TOPBP1 is regulated by HTATSF1. Meanwhile, we demonstrated that HTATSF1 is required for efficient repair of DSBs by HR. Interestingly, we found that HTATSF1 is highly expressed in breast cancer, and HTATSF1 deficiency makes breast cancer cells sensitive to PARP inhibitors. Based on these results, we hypothesize that HTATSF1 determines the accumulation of TOPBP1 at sites of DSBs, thus promoting DNA damage repair and finally endowing tumor cells resistant to DNA damaging agents or PARP inhibitors. However, the molecular details regarding to HTATSF-TOPBP1 binding and the molecular mechanism of how HTATSF1 controls TOPBP1 recruitment remains to be further investigated. This project will not only help us to understand the molecular mechanism of DDR coordination and broaden our understanding of the function of HTATSF1 in genome stability, but also provide a potential target for the treatment of breast cancer.