title: Rad51 activates polyomavirus JC early transcription.
abstract: The human neurotropic polyomavirus JC (JCV) causes the fatal CNS demyelinating disease progressive multifocal leukoencephalopathy (PML). JCV infection is very common and after primary infection, the virus is able to persist in an asymptomatic state. Rarely, and usually only under conditions of immune impairment, JCV re-emerges to actively replicate in the astrocytes and oligodendrocytes of the brain causing PML. The regulatory events involved in the reactivation of active viral replication in PML are not well understood but previous studies have implicated the transcription factor NF-κB acting at a well-characterized site in the JCV noncoding control region (NCCR). NF-κB in turn is regulated in a number of ways including activation by cytokines such as TNF-α, interactions with other transcription factors and epigenetic events involving protein acetylation--all of which can regulate the transcriptional activity of JCV. Active JCV infection is marked by the occurrence of rapid and extensive DNA damage in the host cell and the induction of the expression of cellular proteins involved in DNA repair including Rad51, a major component of the homologous recombination-directed double-strand break DNA repair machinery. Here we show that increased Rad51 expression activates the JCV early promoter. This activation is co-operative with the stimulation caused by NF-κB p65, abrogated by mutation of the NF-κB binding site or siRNA to NFκB p65 and enhanced by the histone deacetylase inhibitor sodium butyrate. These data indicate that the induction of Rad51 resulting from infection with JCV acts through NF-κB via its binding site to stimulate JCV early transcription. We suggest that this provides a novel positive feedback mechanism to enhance viral gene expression during the early stage of JCV infection.
authors.affiliation: Center for Neurovirology, Department of Neuroscience, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Martyn K
authors.initials: MK
authors.lastname: White
authors.affiliation: Center for Neurovirology, Department of Neuroscience, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Rafal
authors.initials: R
authors.lastname: Kaminski
authors.affiliation: Center for Neurovirology, Department of Neuroscience, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Kamel
authors.initials: K
authors.lastname: Khalili
authors.affiliation: Center for Neurovirology, Department of Neuroscience, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Hassen S
authors.initials: HS
authors.lastname: Wollebo
mesh_terms: D020148:Butyric Acid / Q000494:pharmacology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002458:Cell Fractionation; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology; D021901:DNA, Intergenic / Q000235:genetics; D005799:Genes, Dominant; D017930:Genes, Reporter; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007577:JC Virus / Q000187:drug effects / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D020033:Protein Isoforms / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D051135:Rad51 Recombinase / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D016207:Cytokines; D021901:DNA, Intergenic; D020672:I-kappa B Proteins; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D020148:Butyric Acid; D051135:Rad51 Recombinase