• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The protein factors MBNL1 and U2AF65 bind alternative RNA structures to regulate splicing
【24h】

The protein factors MBNL1 and U2AF65 bind alternative RNA structures to regulate splicing

机译：蛋白质因子MBNL1和U2AF65结合其他RNA结构来调节剪接

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Myotonic dystrophy type 1 (DM1) is a genetic disorder linked to a (CTG)_n repeat expansion in the 3' untranslated region of the DMPK gene. Upon transcription in the nucleus, the CUG repeats form a stable RNA stem-loop that sequesters the RNA-binding protein MBNL1 from its normal function in the cell. MBNL1 regulates the alternative splicing of many pre-mRNAs, and upon MBNLVs sequestration, the alternative splicing of many genes is mis-regulated, leading to disease symptoms. MBNL1 is known to bind directly to at least 3 of the pre-mRNAs that it regulates, but how MBNL1 binding mechanistically regulates alternative splicing is unclear. Here, we demonstrate that MBNL1 controls the splicing of exon 5 in the cardiac troponin T (cTNT) pre-mRNA by competing directly with the essential splicing factor U2AF65 for binding at the 3' end of intron 4. When U2AF65 is prevented from binding to the pre-mRNA, the U2 snRNP can no longer be recruited and the following exon is skipped. Furthermore, MBNL1 and U2AF65 appear to compete by binding to mutually exclusive RNA structures. When bound by splicing factors, the 3' end of intron 4 can form either a stem-loop or a single-stranded structure. MBNL1 binds a portion of the intron as a stem-loop, whereas U2AF65 binds the same region in a single-strand structure. Mutations that strengthen the stem-loop decrease U2AF65 binding affinity and also repress exon 5 inclusion, independently of MBNL1. Thus, U2AF65 binding can be blocked either by MBNL1 binding or by the stabilization of RNA secondary structure.
机译：1型强直性肌营养不良症（DM1）是与DMPK基因3'非翻译区的（CTG）_n重复扩增相关的遗传性疾病。在细胞核中转录后，CUG重复序列形成稳定的RNA茎环，将RNA结合蛋白MBNL1从细胞的正常功能中隔离出来。 MBNL1调控许多前mRNA的选择性剪接，而MBNLV隔离后，许多基因的选择性剪接被错误调节，从而导致疾病症状。已知MBNL1直接与其至少调控的3个pre-mRNA结合，但是尚不清楚MBNL1如何机械结合地调控可变剪接。在这里，我们证明MBNL1通过直接与必不可少的剪接因子U2AF65竞争内含子4的3'端结合来控制心肌肌钙蛋白T（cTNT）pre-mRNA中外显子5的剪接。如果是pre-mRNA，则无法再募集U2 snRNP，并且跳过以下外显子。此外，MBNL1和U2AF65似乎通过与相互排斥的RNA结构结合而竞争。当受到剪接因子的限制时，内含子4的3'端可以形成茎环或单链结构。 MBNL1结合内含子的一部分作为茎环，而U2AF65结合单链结构中的相同区域。独立于MBNL1，增强茎环的突变会降低U2AF65的结合亲和力，并抑制外显子5的包涵。因此，U2AF65结合可以被MBNL1结合或RNA二级结构的稳定所阻断。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号