Mechanisms of the spliceosome protein SF3B1 and inhibitors

项目总结 我们研究的长期目标是建立剪接体功能的机制模型。这个 剪接体催化前-mRNA剪接，这是真核基因表达的关键步骤，以及 异常剪接是包括癌症在内的许多人类疾病的基础。理解这一点至关重要 在正常、健康的情况下，细胞机器是确定异常程度的必要第一步 剪接体活性的变化与癌症有关。剪接体由100多种蛋白质组成， 而我们对其中的绝大多数缺乏机械性的信息。其中一个核心剪接体 蛋白质是SF3B1，它在几种不同类型的癌症中经常发生突变。SF3B1也是 天然抗肿瘤产品的靶标。我们的目标是确定剪接体核心的作用 蛋白质SF3B1在剪接体组装过程中的结构及活性测定 SF3B1抑制剂的相互关系。我们将使用体外剪接系统来实现这些目标 表征合成抑制剂类似物的效果。我们对SF3B1的研究意义重大，因为 破译核心剪接体蛋白的功能将填补我们机制中的一个巨大空白 了解拼接过程。此外，了解SF3B1的作用有望 影响积极的研究努力，以揭示癌细胞对剪接的依赖，并向 基于剪接调控的新型化疗药物的研究进展。

PROJECT SUMMARY The long-term goal of our research is to build a mechanistic model of spliceosome function. The spliceosome catalyzes pre-mRNA splicing, which is a crucial step in eukaryotic gene expression, and abnormal splicing underlies many human diseases, including cancers. Understanding this critical cellular machine in normal, healthy situations is the necessary first step to determining how aberrant changes in spliceosome activity is linked to cancer. The spliceosome consists of over 100 proteins, and we lack mechanistic information for the vast majority of them. One of the core spliceosome proteins is SF3B1, which is frequently mutated in several different types of cancer. SF3B1 is also the target of natural anti-tumor products. Our objectives are to determine the role of the spliceosome core protein SF3B1 in the spliceosome assembly process and to determine the structure activity relationships of SF3B1 inhibitors. We will achieve these goals using an in vitro splicing system to characterize the effect of synthetic inhibitor analogs. Our research on SF3B1 is significant because deciphering the function of a core spliceosome protein will fill a large gap in our mechanistic understanding of the splicing process. Furthermore, understanding the role of SF3B1 promises to impact active research efforts to uncover the dependence of cancer cells on splicing, and to inform the development of new chemotherapeutics based on splicing modulation.