title: Oncogenic Herpesvirus Utilizes Stress-Induced Cell Cycle Checkpoints for Efficient Lytic Replication.
abstract: Kaposi's sarcoma herpesvirus (KSHV) causes Kaposi's sarcoma and certain lymphoproliferative malignancies. Latent infection is established in the majority of tumor cells, whereas lytic replication is reactivated in a small fraction of cells, which is important for both virus spread and disease progression. A siRNA screen for novel regulators of KSHV reactivation identified the E3 ubiquitin ligase MDM2 as a negative regulator of viral reactivation. Depletion of MDM2, a repressor of p53, favored efficient activation of the viral lytic transcription program and viral reactivation. During lytic replication cells activated a p53 response, accumulated DNA damage and arrested at G2-phase. Depletion of p21, a p53 target gene, restored cell cycle progression and thereby impaired the virus reactivation cascade delaying the onset of virus replication induced cytopathic effect. Herpesviruses are known to reactivate in response to different kinds of stress, and our study now highlights the molecular events in the stressed host cell that KSHV has evolved to utilize to ensure efficient viral lytic replication.
authors.affiliation: Translational Cancer Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Balistreri
authors.affiliation: Translational Cancer Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Viiliäinen
authors.affiliation: Genome-Scale Biology Program, Research Programs Unit and Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Turunen
authors.affiliation: Translational Cancer Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.
authors.forename: Raquel
authors.initials: R
authors.lastname: Diaz
authors.affiliation: Genome-Scale Biology Program, Research Programs Unit, University of Helsinki, Biomedicum Helsinki, Helsinki, Finland.
authors.forename: Lauri
authors.initials: L
authors.lastname: Lyly
authors.affiliation: Translational Cancer Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.
authors.forename: Pirita
authors.initials: P
authors.lastname: Pekkonen
authors.affiliation: VTT Medical Biotechnology, Turku, Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Rantala
authors.affiliation: Translational Cancer Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.
authors.forename: Krista
authors.initials: K
authors.lastname: Ojala
authors.affiliation: Translational Cancer Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Sarek
authors.affiliation: Translational Cancer Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.
authors.forename: Mari
authors.initials: M
authors.lastname: Teesalu
authors.affiliation: Institute for Molecular Medicine (FIMM), University of Helsinki, Biomedicum Helsinki, Helsinki, Finland.
authors.forename: Oxana
authors.initials: O
authors.lastname: Denisova
authors.affiliation: Centre for Drug Discovery, University of Helsinki, Helsinki, Finland.
authors.forename: Karita
authors.initials: K
authors.lastname: Peltonen
authors.affiliation: Department of Virology, University of Turku and National Institute for Health and Welfare, Turku, Finland.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Julkunen
authors.affiliation: Translational Cancer Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Varjosalo
authors.affiliation: Institute for Molecular Medicine (FIMM), University of Helsinki, Biomedicum Helsinki, Helsinki, Finland.
authors.forename: Denis
authors.initials: D
authors.lastname: Kainov
authors.affiliation: Institute for Molecular Medicine (FIMM), University of Helsinki, Biomedicum Helsinki, Helsinki, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
authors.affiliation: Centre for Drug Discovery, University of Helsinki, Helsinki, Finland.|Department of Radiation Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Marikki
authors.initials: M
authors.lastname: Laiho
authors.affiliation: Genome-Scale Biology Program, Research Programs Unit and Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Jussi
authors.initials: J
authors.lastname: Taipale
authors.affiliation: Genome-Scale Biology Program, Research Programs Unit, University of Helsinki, Biomedicum Helsinki, Helsinki, Finland.
authors.forename: Sampsa
authors.initials: S
authors.lastname: Hautaniemi
authors.affiliation: Translational Cancer Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.|Foundation for the Finnish Cancer Institute, Helsinki, Finland.|Section of Virology, Division of Infectious Diseases, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Päivi M
authors.initials: PM
authors.lastname: Ojala
mesh_terms: D059447:Cell Cycle Checkpoints / Q000235:genetics*; D045744:Cell Line, Tumor; D004261:DNA Replication; D015967:Gene Expression Regulation, Viral / Q000235:genetics*; D019288:Herpesvirus 8, Human / Q000235:genetics*; D006801:Humans; D034741:RNA, Small Interfering / Q000235:genetics; D012514:Sarcoma, Kaposi / Q000378:metabolism / Q000821:virology; D013312:Stress, Physiological / Q000235:genetics*; D014775:Virus Activation / Q000502:physiology; D017735:Virus Latency / Q000235:genetics; D014779:Virus Replication / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering