Abstract
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.
Highlights
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
DoTT for ΔICP27 was substantially reduced compared to the observed alterations in host gene expression infected with the WT HSV-1 (Fig. 1c), suggesting that ICP27 plays a major role in HSV-1-induced DoTT
These data suggest that multiple factors contribute to HSV-1-induced DoTT and that ICP27 plays a major role in this process
Summary
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. We demonstrate that the HSV-1 immediate early protein ICP27 induces DoTT by directly binding to the essential mRNA 3’ processing factor CPSF. 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. Through nascent RNA sequencing, we first demonstrated that lytic herpes simplex virus-1 (HSV-1) infection induces widespread disruption of transcription termination (DoTT) in host genes[13]. ICP27 can act as a sequence-dependent activator of mRNA 3′ processing for viral transcripts These results reveal a critical role for ICP27 in mediating host shut-off during HSV-1 infection
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