Oncogenic Herpesvirus Utilizes Stress-Induced Cell Cycle Checkpoints for Efficient Lytic Replication

PLoS Pathogens

Karita Peltonen¹  Marikki Laiho¹  Jussi Taipale²  Ilkka Julkunen³  Mikko Turunen⁴  Sampsa Hautaniemi⁴  Päivi M. Ojala⁵  Lauri Lyly⁵  Olli Kallioniemi⁶  Oxana Denisova⁶  Denis Kainov⁶  Johanna Viiliäinen⁷  Grzegorz Sarek⁷  Pirita Pekkonen⁷  Krista Ojala⁷  Raquel Diaz⁷  Markku Varjosalo⁷  Mari Teesalu⁷  Giuseppe Balistreri⁷  Juha Rantala⁸ 

[1] 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;Department of Virology, University of Turku and National Institute for Health and Welfare, Turku, Finland;Genome-Scale Biology Program, Research Programs Unit and Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland;Genome-Scale Biology Program, Research Programs Unit, University of Helsinki, Biomedicum Helsinki, Helsinki, Finland;Institute for Molecular Medicine (FIMM), University of Helsinki, Biomedicum Helsinki, Helsinki, Finland;Translational Cancer Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland;VTT Medical Biotechnology, Turku, Finland

关键词: Viral replication;    Fluorescence imaging;    Cell cycle;    cell division;    Small interfering RNAs;    Gene expression;    Image analysis;    DNA damage;    Immunofluorescence;   

DOI  :  10.1371/journal.ppat.1005424

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY