RNA结合蛋白DND1在PGC发育中发挥功能的分子机制

DND1是一类RNA结合蛋白，对原始生殖细胞（PGC）的发育至关重要。DND1可以结合到特定的mRNA上，抑制miRNA与其靶标位点相互作用，从而保护这些转录本免受miRNA介导的翻译阻遏；同时，DND1也可以与NANOS2-CNOT1形成蛋白复合物，通过脱腺苷酸化促进mRNA降解。然而，DND1如何通过调控这两种生物学过程决定RNA分子的最终命运，还不清楚。本项目将致力于解决以下两个问题：1）通过解析DND1-RNA复合物的结构，揭示DND1结合RNA的分子机制；2）通过研究DND1-NANOS2-CNOT1复合物的结构和功能，阐明该复合物特异性降解RNA的生化机理。我们的研究将揭示DND1调控特定基因表达的生化基础，为更深入的理解PGC发育和生殖细胞命运决定提供理论支持，并帮助我们从新的角度认识RNA结合蛋白发挥功能的基础分子生物学机制。

DND1 is an RNA-binding protein essential for germline development. DND1 has both positive and negative regulatory roles in gene expression. On the one hand, DND1 can bind to specific mRNAs and inhibit miRNA association with their target sites, thus protecting these transcripts from miRNA-mediated repression. On the other hand, DND1 can also form protein complexes with NANOS2-CNOT1 to promote mRNA degradation through deadenylation. It is unclear how DND1 precisely regulates these two opposite functions and how DND1 determines the ultimate fate of the bound RNA molecule. In this project, we aim to address these questions by the following studies. (1) Solve the structure of DND1-RNA complex to reveal how DND1 can specifically recognize the target RNA. (2) Elucidate the structural basis and functional roles of DND1-NANOS2-CNOT1 complex to reveal how the complex specifically destabilizes a set of transcripts. The proposed study will provide the first structural insights into the molecular mechanisms by which DND1 regulates a subset of mRNAs and in turn determines the fate of germ cells, and also give us important implications on the general molecular mechanisms by which RNA binding proteins function.