title: Cell cycle modulation by Marek's disease virus: the tegument protein VP22 triggers S-phase arrest and DNA damage in proliferating cells.
abstract: Marek's disease is one of the most common viral diseases of poultry affecting chicken flocks worldwide. The disease is caused by an alphaherpesvirus, the Marek's disease virus (MDV), and is characterized by the rapid onset of multifocal aggressive T-cell lymphoma in the chicken host. Although several viral oncogenes have been identified, the detailed mechanisms underlying MDV-induced lymphomagenesis are still poorly understood. Many viruses modulate cell cycle progression to enhance their replication and persistence in the host cell, in the case of some oncogenic viruses ultimately leading to cellular transformation and oncogenesis. In the present study, we found that MDV, like other viruses, is able to subvert the cell cycle progression by triggering the proliferation of low proliferating chicken cells and a subsequent delay of the cell cycle progression into S-phase. We further identified the tegument protein VP22 (pUL49) as a major MDV-encoded cell cycle regulator, as its vector-driven overexpression in cells lead to a dramatic cell cycle arrest in S-phase. This striking functional feature of VP22 appears to depend on its ability to associate with histones in the nucleus. Finally, we established that VP22 expression triggers the induction of massive and severe DNA damages in cells, which might cause the observed intra S-phase arrest. Taken together, our results provide the first evidence for a hitherto unknown function of the VP22 tegument protein in herpesviral reprogramming of the cell cycle of the host cell and its potential implication in the generation of DNA damages.
authors.affiliation: INRA, UMR1282 Infectiologie et Santé Publique, Equipe Biologie des Virus Aviaires, Nouzilly, France.
authors.forename: Laëtitia
authors.initials: L
authors.lastname: Trapp-Fragnet
authors.affiliation: INRA, UMR1282 Infectiologie et Santé Publique, Equipe Biologie des Virus Aviaires, Nouzilly, France.
authors.forename: Djihad
authors.initials: D
authors.lastname: Bencherit
authors.affiliation: INRA, UMR1282 Infectiologie et Santé Publique, Equipe Biologie des Virus Aviaires, Nouzilly, France.
authors.forename: Danièle
authors.initials: D
authors.lastname: Chabanne-Vautherot
authors.affiliation: INRA, UMR1282 Infectiologie et Santé Publique, Laboratoire de Cytométrie, Nouzilly, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Le Vern
authors.affiliation: INRA, UMR1282 Infectiologie et Santé Publique, Equipe Biologie des Virus Aviaires, Nouzilly, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Remy
authors.affiliation: INRA, UMR 1331, Toxalim, Research Centre in Food Toxicology, Toulouse, France; University of Toulouse, UPS, UMR1331, Toxalim, Toulouse, France.
authors.forename: Elisa
authors.initials: E
authors.lastname: Boutet-Robinet
authors.affiliation: INRA, UMR 1331, Toxalim, Research Centre in Food Toxicology, Toulouse, France; University of Toulouse, UPS, UMR1331, Toxalim, Toulouse, France.
authors.forename: Gladys
authors.initials: G
authors.lastname: Mirey
authors.affiliation: INRA, UMR1282 Infectiologie et Santé Publique, Equipe Biologie des Virus Aviaires, Nouzilly, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Vautherot
authors.affiliation: INRA, UMR1282 Infectiologie et Santé Publique, Equipe Biologie des Virus Aviaires, Nouzilly, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Denesvre
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002645:Chickens; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D006657:Histones / Q000378:metabolism; D025922:Mardivirus / Q000378:metabolism*; D008380:Marek Disease / Q000473:pathology; D021381:Protein Transport; D016196:S Phase; D013347:Subcellular Fractions / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D006657:Histones; D014764:Viral Proteins