一个基于酵母的高通量选平台,用于发现新型mRNA前剪接调节器
Sierra L Love1,2, Henrik Vollmer2, Ya-Chu Chang3,4
1Genetics Training Program, University of Wisconsin-Madison, Madison, WI 53706.
bioRxiv : the preprint server for biology
|November 24, 2025
概括
研究人员开发了一种基于酵母的新型高通量查 (HTS) 平台,以发现调节前信使RNA (前mRNA) 拼接的小分子. 这个平台确定了四种改变拼接的化合物,其中一种在具有特定突变的癌细胞中显示出有前途.
科学领域:
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
- 药物发现 药物发现 药物发现
背景情况:
- 前信使RNA (前mRNA) 拼接对于真核生物的基因表达至关重要.
- 拼接失调与许多疾病有关.
- 很少有能够调节拼接或抑制拼接机械的小分子存在.
研究的目的:
- 建立一个新的高通量选 (HTS) 平台,用于识别拼接调节化合物.
- 发现可以抑制前mRNA拼接的小分子.
- 在癌症模型中研究已识别的化合物的治疗潜力.
主要方法:
- 使用酵母菌 (*S. cerevisiae*) 菌株的双层选方法.
- 主要查:测量敏感酵母菌株的生长抑制.
- 二级屏幕:利用光蛋白质生产作为拼接抑制的读数.
主要成果:
- 鉴定了4种诱导酵母中未连接的前mRNA*in vivo*积累的小分子.
- 一种化合物与野生类型相比,在具有SRSF2P95H突变的癌细胞中显示出增加的敏感性.
- 转录组分析揭示了敏感细胞中广泛的基因表达变化.
结论:
- 基于酵母的HTS平台有效地识别了改变mRNA前拼接结果的化合物.
- 这些已识别的化合物代表了开发针对拼接失调的新疗法的潜在线索.
- 这种方法为在拼接相关疾病中药物发现提供了强大的工具.
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