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Mechanism and consequences of herpes simplex virus 1-mediated regulation of host mRNA alternative polyadenylation

Xiuye Wang, View ORCID ProfileLiang Liu, View ORCID ProfileAdam W. Whisnant, Thomas Hennig, View ORCID ProfileLara Djakovic, View ORCID ProfileNabila Haque, View ORCID ProfileCindy Bach, Rozanne M. Sandri-Goldin, View ORCID ProfileFlorian Erhard, View ORCID ProfileCaroline C. Friedel, Lars Dölken, View ORCID ProfileYongsheng Shi
doi: https://doi.org/10.1101/2020.11.26.399626
Xiuye Wang
1Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA
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Liang Liu
1Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA
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Adam W. Whisnant
2Institute for Virology and Immunobiology, Julius-Maximilians-University Würzburg, Germany
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Thomas Hennig
2Institute for Virology and Immunobiology, Julius-Maximilians-University Würzburg, Germany
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Lara Djakovic
2Institute for Virology and Immunobiology, Julius-Maximilians-University Würzburg, Germany
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Nabila Haque
1Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA
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Cindy Bach
1Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA
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Rozanne M. Sandri-Goldin
1Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA
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Florian Erhard
2Institute for Virology and Immunobiology, Julius-Maximilians-University Würzburg, Germany
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Caroline C. Friedel
3Institute of Informatics, Ludwig-Maximilians-Universität München, Germany
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  • For correspondence: yongshes@uci.edu lars.doelken@vim.uni-wuerzburg.de Caroline.Friedel@bio.ifi.lmu.de
Lars Dölken
2Institute for Virology and Immunobiology, Julius-Maximilians-University Würzburg, Germany
4Helmholtz Institute for RNA-based Infection Research, Würzburg, Germany
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  • For correspondence: yongshes@uci.edu lars.doelken@vim.uni-wuerzburg.de Caroline.Friedel@bio.ifi.lmu.de
Yongsheng Shi
1Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA
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  • For correspondence: yongshes@uci.edu lars.doelken@vim.uni-wuerzburg.de Caroline.Friedel@bio.ifi.lmu.de
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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. Finally, HSV-1-induced mRNAs polyadenylated at intronic PAS 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. Together with other recent studies, our results suggest that viral infection and cellular stresses induce a multi-faceted host shutoff response that includes DoTT and changes in APA profiles.

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Posted November 26, 2020.
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Mechanism and consequences of herpes simplex virus 1-mediated regulation of host mRNA alternative polyadenylation
Xiuye Wang, Liang Liu, Adam W. Whisnant, Thomas Hennig, Lara Djakovic, Nabila Haque, Cindy Bach, Rozanne M. Sandri-Goldin, Florian Erhard, Caroline C. Friedel, Lars Dölken, Yongsheng Shi
bioRxiv 2020.11.26.399626; doi: https://doi.org/10.1101/2020.11.26.399626
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Mechanism and consequences of herpes simplex virus 1-mediated regulation of host mRNA alternative polyadenylation
Xiuye Wang, Liang Liu, Adam W. Whisnant, Thomas Hennig, Lara Djakovic, Nabila Haque, Cindy Bach, Rozanne M. Sandri-Goldin, Florian Erhard, Caroline C. Friedel, Lars Dölken, Yongsheng Shi
bioRxiv 2020.11.26.399626; doi: https://doi.org/10.1101/2020.11.26.399626

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