转录出核复合物的结构与功能研究

真核生物核膜将转录和翻译过程在空间上分隔，mRNA在完成转录和加工之后需要经过核孔复合物出核转运。mRNA转录出核复合物（TREX复合物）广泛存在于真核生物中，参与mRNA的出核转运过程。在高等真核生物中，TREX复合物介导mRNA出核转运具有选择性，其选择性转运mRNA的过程可能作为基因表达调控的一环，参与干细胞命运决定、生物个体胚胎发育和肿瘤发生，TREX复合物组分的表达异常与一些家族性遗传病和癌症相关。由于缺乏高等真核生物中TREX复合物的结构信息，其组装和参与mRNA选择性转运的分子机制尚不明晰。本项目拟以结构生物学入手，解析TREX复合物的结构，获取TREX复合物精确组装的结构基础；明确TREX复合物在生物体内选择性识别转运mRNA的分子机制；探索TREX复合物选择性转运mRNA调控干细胞命运和肿瘤发生发展的分子机制，为相关遗传性疾病和癌症的早期诊断和治疗提供理论依据。

Eukaryotic gene transcription and translation are separated spatially by nuclear membranes. After transcription and post-transcription process, mature mRNA need to transport through nuclear pore complex, this process is facilitated by transcription‑export complex (TREX complex), which exists widely in eukaryotes from yeast to mammals. In higher eukaryotes, like mammals, TREX complex can selectively transport mRNAs which involve in stem cell fate determination, embryonic development and tumor biogenesis. These facts make TREX complex selectively transport mRNA as a participant in regulation of gene expression. The dysregulation of TREX components are related to series of hereditary disease and cancer. Due to the lack of structural information, the molecular mechanism of selective mRNA export by TREX complex is still unclear. In this project, we intend to get structural information of TREX complex by structural biology approaches, investigate the mechanism how TREX complex selectively recognize and export mRNAs by in vitro biochemical methods. Based on these work, we further use cell biology and experimental animal approaches to investigate the molecular mechanism of how TREX complex regulated stem cell fate determination and tumor biogenesis by its selectively mediates mRNA export. We hope this research could provide new theoretical basis for the diagnosis and treatment of relative hereditary disease and cancer.