PAINT非经典翻译途径和primordazine对该途径的抑制机理

原始生殖细胞(PGCs)是生殖细胞的前体，其功能异常会导致不育或生殖细胞肿瘤等疾病。PGCs的形成早于母本到合子的转换时期，因此其产生和维持依赖于短poly(A)尾的母源mRNA的翻译。这些mRNA是如何有效的被翻译的一直是发育生物学上的难题。我们前期的研究在斑马鱼早期胚胎中首次发现了不依赖poly(A)尾的非经典翻译途径PAINT，同时还筛选出特异性抑制PAINT翻译途径但是不影响经典翻译途径的小分子抑制剂primordazine，在处理后的斑马鱼胚胎中能够造成PGCs的缺失。Primordazine的翻译抑制作用依赖于部分特定mRNA中脱去腺苷的3’UTR应答序列（PRE）。在本项目中，我们将从不同角度深入研究PAINT和primordazine的分子机制。该项研究不仅能让我们深入理解基础科学中的一类新发现的生物途径，还可以为例如生殖细胞瘤和不孕不育等相关疾病的治疗提供新思路。

PGCs are precursor germ cells of which dysfunction results in detrimental consequences such as infertility and germ cell tumors. PGCs form with a supply of maternal mRNAs that contain shorter poly(A)-tails before embryos start transcription. How such mRNAs are selectively translated without the benefit of poly(A) tails remains unknown. Our previous study discovered Poly(A)-tail Independent Non-canonical Translation, PAINT, during early embryogenesis, and identified a small molecule primordazine that inhibits only PAINT without affecting canonical translation, leading to PGC loss. Primordazine’s underlying mechanism of action is translational repression mediated by deadenylated PRE-containing 3’UTRs of a specific subgroup of genes. In this project, we propose to elucidate the molecular mechanisms of PAINT process and primordazine’s action on PAINT inhibition. Successful fulfillment of this proposed study will not only provide significant insight into this newly discovered novel biological process, but also may deliver new therapeutic strategies for diseases or critical health conditions such as germ cell tumors and infertility.