Characterization of the aberrant splicing of DVL2 induced by cancer-associated SF3B1 mutation
Characterization of the aberrant splicing of DVL2 induced by cancer-associated SF3B1 mutation
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癌症相关 SF3B1 突变诱导的 DVL2 异常剪接的表征
DOI：
10.1016/j.bbrc.2021.01.084
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发表时间：
2021
影响因子：
3.1
通讯作者：
Youzhong Wan
中科院分区：
文献类型：
--
作者：
Bo Zhao;Xin Hu;Yuning Zhou;Yueru Shi;Rui Qian;Youzhong Wan
SF3B1 是 U2 snRNP 的重要组成部分，在癌症中经常发生突变。癌症相关的 SF3B1 突变会导致异常的 RNA 剪接，主要发生在 3' 剪接位点 (3'ss)。 DVL2（Notch 信号传导的调节因子）的 RNA 剪接受到 SF3B1 突变的影响。在这里，我们报道突变的SF3B1使用替代分支点序列（BPS）来进行DVL2的异常剪接，其对U2 snRNA的亲和力比用于DVL2的规范剪接的BPS更高。将替代 BPS 的位置与规范 BPS 的位置交换会减少 DVL2 的异常剪接，表明突变的 SF3B1 更喜欢使用与 U2 snRNA 具有高亲和力的 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，与 U2 snRNA 的亲和力以及与 3's 的距离对于 BPS 的选择都很重要。重要的是，DVL2的异常剪接不需要典型的3's和典型的多嘧啶束，这揭示了SF3B1突变诱导的一种新型异常剪接。这些发现提供了对癌症中 SF3B1 突变诱导的异常剪接机制的更全面的了解。
SF3B1, an essential component of the U2 snRNP, is frequently mutated in cancers. Cancer-associatedSF3B1mutation causes aberrant RNA splicing, mostly at 3′ splice sites (3’ss). RNA splicing ofDVL2, a regulator of Notch signaling, is affected bySF3B1mutation. Here, we report that the mutated SF3B1 use an alternative branchpoint sequence (BPS) for the aberrant splicing ofDVL2, which has a higher affinity to U2 snRNA than the BPS for the canonical splicing ofDVL2. Swapping the position of the alternative BPS with the position of the canonical BPS decreased the aberrant splicing ofDVL2, 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 ofDVL2demonstrated 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 ofDVL2does 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.