Living Systems Institute, University of Exeter, Stocker Road, Exeter, EX4 4QD, United Kingdom.
Cell Biology Centre, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8503, Japan.
Mol Cell. 2023 Jul 6;83(13):2222-2239.e5. doi: 10.1016/j.molcel.2023.05.029. Epub 2023 Jun 16.
The transcriptional termination of unstable non-coding RNAs (ncRNAs) is poorly understood compared to coding transcripts. We recently identified ZC3H4-WDR82 ("restrictor") as restricting human ncRNA transcription, but how it does this is unknown. Here, we show that ZC3H4 additionally associates with ARS2 and the nuclear exosome targeting complex. The domains of ZC3H4 that contact ARS2 and WDR82 are required for ncRNA restriction, suggesting their presence in a functional complex. Consistently, ZC3H4, WDR82, and ARS2 co-transcriptionally control an overlapping population of ncRNAs. ZC3H4 is proximal to the negative elongation factor, PNUTS, which we show enables restrictor function and is required to terminate the transcription of all major RNA polymerase II transcript classes. In contrast to short ncRNAs, longer protein-coding transcription is supported by U1 snRNA, which shields transcripts from restrictor and PNUTS at hundreds of genes. These data provide important insights into the mechanism and control of transcription by restrictor and PNUTS.
与编码转录本相比，不稳定的非编码 RNA（ncRNA）的转录终止机制研究还不够深入。我们最近发现 ZC3H4-WDR82（“限制因子”）可以限制人类 ncRNA 的转录，但它的具体作用机制尚不清楚。在这里，我们表明 ZC3H4 还与 ARS2 和核外切体靶向复合物结合。与 ARS2 和 WDR82 接触的 ZC3H4 结构域对于 ncRNA 的限制是必需的，这表明它们存在于一个功能性复合物中。一致地，ZC3H4、WDR82 和 ARS2 共同转录调控重叠的 ncRNA 群体。ZC3H4 接近负延伸因子 PNUTS，我们表明 PNUTS 能够赋予限制因子功能，并需要终止所有主要 RNA 聚合酶 II 转录物类别的转录。与短 ncRNA 不同，较长的蛋白质编码转录由 U1 snRNA 支持，它可以在数百个基因中阻止限制因子和 PNUTS 与转录物结合。这些数据为限制因子和 PNUTS 的转录机制和调控提供了重要的见解。
