title: Widespread disruption of host transcription termination in HSV-1 infection.
abstract: Herpes simplex virus 1 (HSV-1) is an important human pathogen and a paradigm for virus-induced host shut-off. Here we show that global changes in transcription and RNA processing and their impact on translation can be analysed in a single experimental setting by applying 4sU-tagging of newly transcribed RNA and ribosome profiling to lytic HSV-1 infection. Unexpectedly, we find that HSV-1 triggers the disruption of transcription termination of cellular, but not viral, genes. This results in extensive transcription for tens of thousands of nucleotides beyond poly(A) sites and into downstream genes, leading to novel intergenic splicing between exons of neighbouring cellular genes. As a consequence, hundreds of cellular genes seem to be transcriptionally induced but are not translated. In contrast to previous reports, we show that HSV-1 does not inhibit co-transcriptional splicing. Our approach thus substantially advances our understanding of HSV-1 biology and establishes HSV-1 as a model system for studying transcription termination.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Rutkowski
authors.affiliation: Institut für Informatik, Ludwig-Maximilians-Universität München, Amalienstraße 17, 80333 München, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Erhard
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: L'Hernault
authors.affiliation: Institut für Informatik, Ludwig-Maximilians-Universität München, Amalienstraße 17, 80333 München, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bonfert
authors.affiliation: Institut für Klinische Molekularbiologie, Christian-Albrechts-Universität Kiel, Schittenhelmstraße 12, 24105 Kiel, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schilhabel
authors.affiliation: Division of Virology, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Crump
authors.affiliation: Institut für Klinische Molekularbiologie, Christian-Albrechts-Universität Kiel, Schittenhelmstraße 12, 24105 Kiel, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
authors.affiliation: Division of Virology, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
authors.forename: Stacey
authors.initials: S
authors.lastname: Efstathiou
authors.affiliation: Institut für Informatik, Ludwig-Maximilians-Universität München, Amalienstraße 17, 80333 München, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Zimmer
authors.affiliation: Institut für Informatik, Ludwig-Maximilians-Universität München, Amalienstraße 17, 80333 München, Germany.
authors.forename: Caroline C
authors.initials: CC
authors.lastname: Friedel
authors.affiliation: 1] Division of Infectious Diseases, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK [2] Institut für Virologie, Julius-Maximilians-Universität Würzburg, Versbacher Straße 7, 97078 Würzburg, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Dölken
mesh_terms: D017398:Alternative Splicing; D018388:Codon, Terminator; D003470:Culture Media; D005091:Exons; D005347:Fibroblasts / Q000378:metabolism / Q000821:virology; D015967:Gene Expression Regulation, Viral; D005814:Genes, Viral; D016679:Genome, Viral; D006561:Herpes Simplex / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D007438:Introns; D016366:Open Reading Frames; D011061:Poly A; D014176:Protein Biosynthesis; D012313:RNA / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D012270:Ribosomes / Q000648:ultrastructure; D013997:Time Factors; D014158:Transcription, Genetic; D014779:Virus Replication / Q000235:genetics
chemical_list: D018388:Codon, Terminator; D003470:Culture Media; D012333:RNA, Messenger; D011061:Poly A; D012313:RNA