Characterization of the aberrant splicing of MAP3K7 induced by cancer-associated SF3B1 mutation
Characterization of the aberrant splicing of MAP3K7 induced by cancer-associated SF3B1 mutation
复制标题
癌症相关 SF3B1 突变诱导的 MAP3K7 异常剪接的表征
DOI：
10.1093/jb/mvab023
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发表时间：
2021-03-05
影响因子：
2.7
通讯作者：
Wan, Youzhong
中科院分区：
文献类型：
--
作者：
Li, Zhuang;Zhao, Bo;Wan, Youzhong
SF3B1是一种重要的RNA剪接因子，在各种类型的癌症中经常发生突变，并且癌症相关的SF3B1突变导致异常RNA剪接。包括MAP3K7在内的几种转录物的异常剪接促进肿瘤发生。在这里，我们确定了一个提前终止密码子异常剪接转录的MAP3K7。用放线菌酮处理用K700 E突变的SF3B1转染的HEK293 T细胞导致MAP3K7的异常剪接转录物的积累增加，表明MAP3K7的异常剪接转录物被无义介导的衰变靶向。异常剪接的MAP3K7转录物使用异常3'剪接位点和替代分支点序列。此外，MAP3K7的异常剪接不仅需要与正常剪接相关的多聚嘧啶段，而且需要异常3'剪接位点上游的替代性多聚嘧啶段。其他癌症相关的SF3B1突变也会导致MAP3K7的异常剪接，这取决于相同的序列特征。我们的数据提供了进一步的理解的机制，潜在的异常剪接诱导的癌症相关的SF3B1突变，并揭示了在疾病中的重要作用的选择性多聚嘧啶道。
SF3B1, an essential RNA splicing factor, is frequently mutated in various types of cancers, and the cancer-associated SF3B1 mutation causes aberrant RNA splicing. The aberrant splicing of several transcripts, including MAP3K7, promotes tumorigenesis. Here, we identify a premature termination codon in the aberrantly spliced transcript of MAP3K7. Treatment of HEK293T cells transfected with the K700E-mutated SF3B1 with cycloheximide leads to increased accumulation of the aberrant spliced transcript of MAP3K7, demonstrating that the aberrantly spliced transcript of MAP3K7 is targeted by nonsense-mediated decay. The aberrantly spliced MAP3K7 transcript uses an aberrant 3' splice sites and an alternative branchpoint sequence. In addition, the aberrant splicing of MAP3K7 requires not only the polypyrimidine tract associated with normal splicing but also an alternative polypyrimidine tract upstream of the aberrant 3' splice site. Other cancer-associated SF3B1 mutations also cause the aberrant splicing of MAP3K7, which depends on the same sequence features. Our data provide a further understanding of the mechanisms underlying aberrant splicing induced by cancer-associated SF3B1 mutation, and reveal an important role of alternative polypyrimidine tract in diseases.