title: HSV-1 remodels host telomeres to facilitate viral replication.
abstract: Telomeres protect the ends of cellular chromosomes. We show here that infection with herpes simplex virus 1 (HSV-1) results in chromosomal structural aberrations at telomeres and the accumulation of telomere dysfunction-induced DNA damage foci (TIFs). At the molecular level, HSV-1 induces transcription of telomere repeat-containing RNA (TERRA), followed by the proteolytic degradation of the telomere protein TPP1 and loss of the telomere repeat DNA signal. The HSV-1-encoded E3 ubiquitin ligase ICP0 is required for TERRA transcription and facilitates TPP1 degradation. Small hairpin RNA (shRNA) depletion of TPP1 increases viral replication, indicating that TPP1 inhibits viral replication. Viral replication protein ICP8 forms foci that coincide with telomeric proteins, and ICP8-null virus failed to degrade telomere DNA signal. These findings suggest that HSV-1 reorganizes telomeres to form ICP8-associated prereplication foci and to promote viral genomic replication.
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Deng
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine and The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Eui Tae
authors.initials: ET
authors.lastname: Kim
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Vladimirova
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Jayaraju
authors.initials: J
authors.lastname: Dheekollu
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Wang
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Alyshia
authors.initials: A
authors.lastname: Newhart
authors.affiliation: Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Liu
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Jaclyn L
authors.initials: JL
authors.lastname: Myers
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Hensley
authors.affiliation: Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Moffat
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Janicki
authors.affiliation: Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Nigel W
authors.initials: NW
authors.lastname: Fraser
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Knipe
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine and The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Weitzman
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: lieberman@wistar.org.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Lieberman
mesh_terms: D002460:Cell Line; D002869:Chromosome Aberrations; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid; D057057:Serine Proteases / Q000235:genetics / Q000378:metabolism; D000089804:Shelterin Complex / Q000378:metabolism; D016615:Telomere / Q000737:chemistry / Q000235:genetics / Q000821:virology*; D034501:Telomere-Binding Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication
chemical_list: C495876:ACD protein, human; D004268:DNA-Binding Proteins; C045462:ICP8 protein, Simplexvirus; D017874:Immediate-Early Proteins; D022661:RNA, Untranslated; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D014764:Viral Proteins; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1; D057057:Serine Proteases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases