China-Japan Union Hospital of Jilin University, Jilin University, Changchun, Jilin, 130033, China; School of Life Sciences, Jilin University, Changchun, Jilin, 130012, China.
China-Japan Union Hospital of Jilin University, Jilin University, Changchun, Jilin, 130033, China.
Biochem Biophys Res Commun. 2021 Mar 26;546:21-28. doi: 10.1016/j.bbrc.2021.01.084. Epub 2021 Feb 6.
SF3B1, an essential component of the U2 snRNP, is frequently mutated in cancers. Cancer-associated SF3B1 mutation causes aberrant RNA splicing, mostly at 3' splice sites (3'ss). RNA splicing of DVL2, a regulator of Notch signaling, is affected by SF3B1 mutation. Here, we report that the mutated SF3B1 use an alternative branchpoint sequence (BPS) for the aberrant splicing of DVL2, which has a higher affinity to U2 snRNA than the BPS for the canonical splicing of DVL2. Swapping the position of the alternative BPS with the position of the canonical BPS decreased the aberrant splicing of DVL2, suggesting that the mutated SF3B1 prefers to use BPS with high affinity to U2 snRNA for splicing. Additionally, swapping the positions of two BPSs associated with the canonical splicing of DVL2 demonstrated that both the affinity to the U2 snRNA and the distance to the 3'ss are important to the selection of BPS. Importantly, the aberrant splicing of DVL2 does not require the canonical 3'ss and the canonical polypyrimidine tract, which reveals a novel type of aberrant splicing induced by SF3B1 mutation. These findings provide a more comprehensive understanding of the mechanisms underlying aberrant splicing induced by SF3B1 mutation in cancer.
SF3B1 是 U2 snRNP 的一个必需组成部分，在癌症中经常发生突变。与癌症相关的 SF3B1 突变导致异常的 RNA 剪接，主要发生在 3' 剪接位点 (3'ss)。Notch 信号通路的调节因子 DVL2 的 RNA 剪接受到 SF3B1 突变的影响。在这里，我们报告说突变的 SF3B1 为 DVL2 的异常剪接使用替代分支点序列 (BPS)，该替代 BPS 与用于 DVL2 规范剪接的 BPS 相比，与 U2 snRNA 的亲和力更高。将替代 BPS 的位置与规范 BPS 的位置交换会降低 DVL2 的异常剪接，这表明突变的 SF3B1 更倾向于使用与 U2 snRNA 亲和力高的 BPS 进行剪接。此外，交换与 DVL2 规范剪接相关的两个 BPS 的位置表明，U2 snRNA 的亲和力和到 3'ss 的距离对于 BPS 的选择都很重要。重要的是，DVL2 的异常剪接不需要规范的 3'ss 和规范的多嘧啶序列，这揭示了由 SF3B1 突变诱导的新型异常剪接类型。这些发现为理解癌症中 SF3B1 突变诱导的异常剪接机制提供了更全面的认识。
