Infection by viruses, including herpes simplex virus-1 (HSV-1), and cellular stresses cause widespread disruption of transcription termination (DoTT) of RNA polymerase II (RNAPII) in host genes. However, the underlying mechanisms remain unclear. Here, we demonstrate that the HSV-1 immediate early protein ICP27 induces DoTT by directly binding to the essential mRNA 3' processing factor CPSF. It thereby induces the assembly of a dead-end 3' processing complex, blocking mRNA 3' cleavage. Remarkably, ICP27 also acts as a sequence-dependent activator of mRNA 3' processing for viral and a subset of host transcripts. Our results unravel a bimodal activity of ICP27 that plays a key role in HSV-1-induced host shutoff and identify CPSF as an important factor that mediates regulation of transcription termination. These findings have broad implications for understanding the regulation of transcription termination by other viruses, cellular stress and cancer.

中文翻译：

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单纯疱疹病毒通过ICP27的双峰活性阻断宿主转录终止。

包括单纯疱疹病毒1（HSV-1）在内的病毒感染和细胞应激会导致宿主基因中RNA聚合酶II（RNAPII）的转录终止（DoTT）广泛破坏。但是，其潜在机制仍不清楚。在这里，我们证明了HSV-1立即早期蛋白ICP27通过直接结合必需的mRNA 3'加工因子CPSF诱导DoTT。因此，它诱导了末端3'加工复合物的装配，阻断了mRNA 3'的切割。值得注意的是，ICP27还充当病毒和部分宿主转录本的mRNA 3'加工的序列依赖性激活剂。我们的研究结果揭示了ICP27的双峰活性，该双峰活性在HSV-1诱导的宿主关闭中起关键作用，并确定CPSF是介导转录终止调控的重要因素。