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Induction of DNA Damages upon Marek's Disease Virus Infection: Implication in Viral Replication and Pathogenesis.

Abstract Marek's disease virus (MDV) is a highly contagious alphaherpesvirus that infects chickens and causes a deadly neoplastic disease. We previously demonstrated that MDV infection arrests cells in S phase and that the tegument protein VP22 plays a major role in this process. In addition, expression of VP22 induces double-strand breaks (DSBs) in the cellular DNA, suggesting that DNA damage and the associated cellular response might be favorable for the MDV life cycle. Here, we addressed the role of DNA damage in MDV replication and pathogenesis. We demonstrated that MDV induces DSBs during lytic infection in vitro and in the peripheral blood mononuclear cells of infected animals. Intriguingly, we did not observe DNA damage in latently infected MDV-induced lymphoblastoid cells, while MDV reactivation resulted in the onset of DNA lesions, suggesting that DNA damage and/or the resulting DNA damage response might be required for efficient MDV replication and reactivation. In addition, reactivation was significantly enhanced by the induction of DNA damage using a number of chemicals. Finally, we used recombinant viruses to show that VP22 is required for the induction of DNA damage in vivo and that this likely contributes to viral oncogenesis.IMPORTANCE Marek's disease virus is an oncogenic alphaherpesvirus that causes fatal T-cell lymphomas in chickens. MDV causes substantial losses in the poultry industry and is also used in small-animal models for virus-induced tumor formation. DNA damage not only is implicated in tumor development but also aids in the life cycle of several viruses; however, its role in MDV replication, latency, and reactivation remains elusive. Here, we demonstrate that MDV induces DNA lesions during lytic replication in vitro and in vivo DNA damage was not observed in latently infected cells; however, it was reinitiated during reactivation. Reactivation was significantly enhanced by the induction of DNA damage. Recombinant viruses that lacked the ability to induce DNA damage were defective in their ability to induce tumors, suggesting that DNA damage might also contribute to cellular transformation processes leading to MDV lymphomagenesis.
PMID
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Authors

Mayor MeshTerms

DNA Breaks, Double-Stranded

Virus Replication

Keywords

DNA damage

Marek's disease virus

VP22

cell cycle

herpesvirus

oncogenesis

viral replication

Journal Title journal of virology
Publication Year Start




PMID- 28978699
OWN - NLM
STAT- MEDLINE
DCOM- 20171215
LR  - 20171215
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Linking)
VI  - 91
IP  - 24
DP  - 2017 Dec 15
TI  - Induction of DNA Damages upon Marek's Disease Virus Infection: Implication in
      Viral Replication and Pathogenesis.
LID - e01658-17 [pii]
LID - 10.1128/JVI.01658-17 [doi]
AB  - Marek's disease virus (MDV) is a highly contagious alphaherpesvirus that infects 
      chickens and causes a deadly neoplastic disease. We previously demonstrated that 
      MDV infection arrests cells in S phase and that the tegument protein VP22 plays a
      major role in this process. In addition, expression of VP22 induces double-strand
      breaks (DSBs) in the cellular DNA, suggesting that DNA damage and the associated 
      cellular response might be favorable for the MDV life cycle. Here, we addressed
      the role of DNA damage in MDV replication and pathogenesis. We demonstrated that 
      MDV induces DSBs during lytic infection in vitro and in the peripheral blood
      mononuclear cells of infected animals. Intriguingly, we did not observe DNA
      damage in latently infected MDV-induced lymphoblastoid cells, while MDV
      reactivation resulted in the onset of DNA lesions, suggesting that DNA damage
      and/or the resulting DNA damage response might be required for efficient MDV
      replication and reactivation. In addition, reactivation was significantly
      enhanced by the induction of DNA damage using a number of chemicals. Finally, we 
      used recombinant viruses to show that VP22 is required for the induction of DNA
      damage in vivo and that this likely contributes to viral oncogenesis.IMPORTANCE
      Marek's disease virus is an oncogenic alphaherpesvirus that causes fatal T-cell
      lymphomas in chickens. MDV causes substantial losses in the poultry industry and 
      is also used in small-animal models for virus-induced tumor formation. DNA damage
      not only is implicated in tumor development but also aids in the life cycle of
      several viruses; however, its role in MDV replication, latency, and reactivation 
      remains elusive. Here, we demonstrate that MDV induces DNA lesions during lytic
      replication in vitro and in vivo DNA damage was not observed in latently infected
      cells; however, it was reinitiated during reactivation. Reactivation was
      significantly enhanced by the induction of DNA damage. Recombinant viruses that
      lacked the ability to induce DNA damage were defective in their ability to induce
      tumors, suggesting that DNA damage might also contribute to cellular
      transformation processes leading to MDV lymphomagenesis.
CI  - Copyright (c) 2017 American Society for Microbiology.
FAU - Bencherit, Djihad
AU  - Bencherit D
AD  - INRA, UMR1282 Infectiologie et Sante Publique, Equipe Biologie des Virus
      Aviaires, Nouzilly, France.
FAU - Remy, Sylvie
AU  - Remy S
AD  - INRA, UMR1282 Infectiologie et Sante Publique, Equipe Biologie des Virus
      Aviaires, Nouzilly, France.
FAU - Le Vern, Yves
AU  - Le Vern Y
AD  - INRA, UMR1282 Infectiologie et Sante Publique, Laboratoire de Cytometrie,
      Nouzilly, France.
FAU - Vychodil, Tereza
AU  - Vychodil T
AD  - Institut fur Virologie, Freie Universitaet Berlin, Berlin, Germany.
FAU - Bertzbach, Luca D
AU  - Bertzbach LD
AD  - Institut fur Virologie, Freie Universitaet Berlin, Berlin, Germany.
FAU - Kaufer, Benedikt B
AU  - Kaufer BB
AD  - Institut fur Virologie, Freie Universitaet Berlin, Berlin, Germany.
FAU - Denesvre, Caroline
AU  - Denesvre C
AD  - INRA, UMR1282 Infectiologie et Sante Publique, Equipe Biologie des Virus
      Aviaires, Nouzilly, France.
FAU - Trapp-Fragnet, Laetitia
AU  - Trapp-Fragnet L
AD  - INRA, UMR1282 Infectiologie et Sante Publique, Equipe Biologie des Virus
      Aviaires, Nouzilly, France [email protected]
LA  - eng
PT  - Journal Article
DEP - 20171130
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (DNA, Viral)
RN  - 0 (UL49 protein, Marek's disease virus type 1)
RN  - 0 (Viral Proteins)
SB  - IM
MH  - Animals
MH  - Cell Cycle/genetics
MH  - Cell Transformation, Neoplastic/genetics
MH  - Cell Transformation, Viral/genetics
MH  - Chickens
MH  - *DNA Breaks, Double-Stranded
MH  - DNA, Viral
MH  - Herpesvirus 2, Gallid/genetics/*pathogenicity/physiology
MH  - Leukocytes, Mononuclear/pathology/virology
MH  - Marek Disease/*genetics/physiopathology/*virology
MH  - Poultry Diseases/virology
MH  - Viral Proteins/genetics
MH  - Virus Activation
MH  - *Virus Replication
PMC - PMC5709610
OTO - NOTNLM
OT  - DNA damage
OT  - Marek's disease virus
OT  - VP22
OT  - cell cycle
OT  - herpesvirus
OT  - oncogenesis
OT  - viral replication
EDAT- 2017/10/06 06:00
MHDA- 2017/12/16 06:00
CRDT- 2017/10/06 06:00
PMCR- 2018/05/30 00:00
PHST- 2017/09/19 00:00 [received]
PHST- 2017/09/26 00:00 [accepted]
PHST- 2018/05/30 00:00 [pmc-release]
PHST- 2017/10/06 06:00 [pubmed]
PHST- 2017/12/16 06:00 [medline]
PHST- 2017/10/06 06:00 [entrez]
AID - JVI.01658-17 [pii]
AID - 10.1128/JVI.01658-17 [doi]
PST - epublish
SO  - J Virol. 2017 Nov 30;91(24). pii: JVI.01658-17. doi: 10.1128/JVI.01658-17. Print 
      2017 Dec 15.