Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117549, Singapore.
Nat Commun. 2022 Apr 4;13(1):1793. doi: 10.1038/s41467-022-29400-7.
The dynamic regulation of alternative splicing requires coordinated participation of multiple RNA binding proteins (RBPs). Aberrant splicing caused by dysregulation of splicing regulatory RBPs is implicated in numerous cancers. Here, we reveal a frequently overexpressed cancer-associated protein, DAP3, as a splicing regulatory RBP in cancer. Mechanistically, DAP3 coordinates splicing regulatory networks, not only via mediating the formation of ribonucleoprotein complexes to induce substrate-specific splicing changes, but also via modulating splicing of numerous splicing factors to cause indirect effect on splicing. A pan-cancer analysis of alternative splicing across 33 TCGA cancer types identified DAP3-modulated mis-splicing events in multiple cancers, and some of which predict poor prognosis. Functional investigation of non-productive splicing of WSB1 provides evidence for establishing a causal relationship between DAP3-modulated mis-splicing and tumorigenesis. Together, our work provides critical mechanistic insights into the splicing regulatory roles of DAP3 in cancer development.
可变剪接的动态调控需要多种 RNA 结合蛋白（RBPs）的协调参与。剪接调控 RBPs 失调导致的剪接异常与许多癌症有关。在这里，我们揭示了一种经常过表达的癌相关蛋白 DAP3，它是癌症中的一种剪接调控 RBP。从机制上讲，DAP3 协调剪接调控网络，不仅通过介导核糖核蛋白复合物的形成来诱导底物特异性剪接变化，还通过调节许多剪接因子的剪接来间接影响剪接。对 33 种 TCGA 癌症类型的剪接进行的泛癌症分析鉴定了 DAP3 调节的多种癌症中的错误剪接事件，其中一些与预后不良相关。对 WSB1 的无义剪接的功能研究为 DAP3 调节的错误剪接与肿瘤发生之间的因果关系提供了证据。总之，我们的工作为 DAP3 在癌症发展中的剪接调控作用提供了重要的机制见解。
