title: Latency of Epstein-Barr virus is disrupted by gain-of-function mutant cellular AP-1 proteins that preferentially bind methylated DNA.
abstract: ZEBReplication Activator (ZEBRA), a viral basic zipper protein that initiates the Epstein-Barr viral lytic cycle, binds to DNA and activates transcription through heptamer ZEBRA response elements (ZREs) related to AP-1 sites. A component of the biologic action of ZEBRA is attributable to binding methylated CpGs in ZREs present in the promoters of viral lytic cycle genes. Residue S186 of ZEBRA, Z(S186), which is absolutely required for disruption of latency, participates in the recognition of methylated DNA. We find that mutant cellular AP-1 proteins, Jun(A266S) and Fos(A151S), with alanine-to-serine substitutions homologous to Z(S186), exhibit altered DNA-binding affinity and preferentially bind methylated ZREs. These mutant AP-1 proteins acquire functions of ZEBRA; they activate expression of many viral early lytic cycle gene transcripts in cells harboring latent EBV but are selectively defective in activating expression of some viral proteins and are unable to promote viral DNA replication. Transcriptional activation by mutant c-Jun and c-Fos that have acquired the capacity to bind methylated CpG challenges the paradigm that DNA methylation represses gene expression.
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Kuan-Ping
authors.initials: KP
authors.lastname: Yu
authors.forename: Lee
authors.initials: L
authors.lastname: Heston
authors.forename: Richard
authors.initials: R
authors.lastname: Park
authors.forename: Zhaowei
authors.initials: Z
authors.lastname: Ding
authors.forename: Ruth
authors.initials: R
authors.lastname: Wang'ondu
authors.forename: Henri-Jacques
authors.initials: HJ
authors.lastname: Delecluse
authors.forename: George
authors.initials: G
authors.lastname: Miller
mesh_terms: D000595:Amino Acid Sequence; D002051:Burkitt Lymphoma / Q000378:metabolism; D045744:Cell Line, Tumor; D019175:DNA Methylation; D015967:Gene Expression Regulation, Viral; D057809:HEK293 Cells; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D017434:Protein Structure, Tertiary; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D017735:Virus Latency
chemical_list: C063676:BZLF1 protein, Herpesvirus 4, Human; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D015534:Trans-Activators