Abstract
Eukaryotic gene expression is extensively regulated by cellular stress and pathogen infections. We have previously shown that herpes simplex virus 1 (HSV-1) and several cellular stresses cause widespread disruption of transcription termination (DoTT) of RNA polymerase II (RNAPII) in host genes and that the viral immediate early factor ICP27 plays an important role in HSV-1-induced DoTT. Here, we show that HSV-1 infection also leads to widespread changes in alternative polyadenylation (APA) of host mRNAs. In the majority of cases, polyadenylation shifts to upstream poly(A) sites (PAS), including many intronic PAS. Mechanistically, ICP27 contributes to HSV-1-mediated APA regulation. HSV-1- and ICP27-induced activation of intronic PAS is sequence-dependent and does not involve general inhibition of U1 snRNP. HSV1-induced intronic polyadenylation is accompanied by early termination of RNAPII. HSV-1-induced mRNAs polyadenylated at intronic PAS (IPA) are exported into the cytoplasm while APA isoforms with extended 3’ UTRs are sequestered in the nuclei, both preventing the expression of the full-length gene products. Finally we provide evidence that HSV-induced IPA isoforms are translated. Together with other recent studies, our results suggest that viral infection and cellular stresses induce a multi-faceted host response that includes DoTT and changes in APA profiles.
Highlights
The 3’ ends of the vast majority of eukaryotic mRNAs are formed through cleavage and polyadenylation [1,2,3]
We have previously shown that herpes simplex virus-1 (HSV-1) blocks host cell transcription termination, at least in part, through the viral immediate early protein ICP27
We show that herpes simplex virus 1 (HSV-1) infection alters mRNA 3’ end formation and promotes the formation of truncated mRNAs
Summary
The 3’ ends of the vast majority of eukaryotic mRNAs are formed through cleavage and polyadenylation [1,2,3]. Poly(A) sites (PAS) are defined by several cis-elements, including the AAUAAA hexamer, the U/GU-rich downstream element, and other auxiliary sequences. These sequences recruit RNA 3’ processing factors CPSF, CstF, CFIm, CFIIm, and the poly(A) polymerase to form the 3’ processing complex. RNA 3’ processing occurs co-transcriptionally and it plays an essential role in RNA biogenesis, and in transcription termination by RNA polymerase II (RNAPII) [4,5,6]. Xrn2-mediated degradation of the nascent RNA leads to transcription termination. In both models, RNA 3’ processing plays a central role in transcription termination
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