Scholarlink

<p>Risdiplam and branaplam represent two classes of small-molecule splicing modulators that promote U1 snRNP recognition of weak non-canonical GA/GU-containing 5’ splice sites (ss). We demonstrate that branaplam enhances recognition of these 5’ ss by reconstituted U1 snRNP in vitro, and that this effect depends on the ZnF domain of U1C and Helix H of U1 snRNA, but not U1A or U1-70K. We also demonstrate that branaplam enhances the weak 5’ ss recognition through a dual act of strengthening the U1 snRNP–5’ ss interaction and U1 snRNP–U1C interaction. In cells, depletion of U1C reduces or abolishes compound-induced exon inclusion for most cassette exons. Interestingly, a subset of cassette exons become responsive to compound only upon U1C knockdown, supporting a model in which U1C stabilizes specific conformations at the 5’ ss–U1 snRNA interface in a context-dependent manner that can either facilitate or hinder compound binding. Surprisingly, risdiplam shows no effect on weak 5’ ss recognition in vitro, suggesting additional cellular factors are required for its activity.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

The U1 snRNP protein U1C and Helix H of U1 snRNA are critical for small molecule splicing modulator function

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月16日

查看全文
  • Zhiling Kuang,
  • Brian Kosmyna,
  • Xueni Li,
  • Zhichao Tang,
  • Shasha Shi,
  • Karoline Lambert,
  • Wenzheng Zhang,
  • Joseph Giovinazzo,
  • Kerstin A. Effenberger,
  • Jairo Sierra,
  • Lanqing Ying,
  • Scott J. Barraza,
  • Wencheng Li,
  • Jingxin Wang,
  • Christopher R. Trotta,
  • Rui Zhao

摘要

Risdiplam and branaplam represent two classes of small-molecule splicing modulators that promote U1 snRNP recognition of weak non-canonical GA/GU-containing 5’ splice sites (ss). We demonstrate that branaplam enhances recognition of these 5’ ss by reconstituted U1 snRNP in vitro, and that this effect depends on the ZnF domain of U1C and Helix H of U1 snRNA, but not U1A or U1-70K. We also demonstrate that branaplam enhances the weak 5’ ss recognition through a dual act of strengthening the U1 snRNP–5’ ss interaction and U1 snRNP–U1C interaction. In cells, depletion of U1C reduces or abolishes compound-induced exon inclusion for most cassette exons. Interestingly, a subset of cassette exons become responsive to compound only upon U1C knockdown, supporting a model in which U1C stabilizes specific conformations at the 5’ ss–U1 snRNA interface in a context-dependent manner that can either facilitate or hinder compound binding. Surprisingly, risdiplam shows no effect on weak 5’ ss recognition in vitro, suggesting additional cellular factors are required for its activity.