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Edward M. Johnson , PhD

    • Title:
    • Professor

    • Role:
    • Faculty

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    • Focus Areas:
    •  AIDS, DNA replication, neurovirology, virology, environmental carcinogenesis, nucleic acids, cancer, cell cycle, tumor suppressors, lung cancer, chromatin,  gene, transcription, brain pathology, HIV.

    • Office Location:
    • Lewis Hall

    • Undergraduate Education:
    • Graduate Education:
      • PhD, Yale University, New Haven, CT
    • Postdoctoral Education:
      • Postdoctoral Training, The Rockefeller University, New York, NY Memorial Sloan-Kettering Cancer Center, New York, NY
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    • Research Interests:
    • Work in the laboratory of Dr. Edward M. Johnson is concerned with control of DNA replication in cancer and AIDS. An important current project involves an opportunistic infection of the brain, caused by the virus JCV, in AIDS patients. We have hypothesized that activation of JCV in glial cells of the brain is influenced by HIV-1 infection. We have found that JCV late gene transcription is stimulated by the HIV-1 Tat protein through action at sequence elements bound by the cellular protein, Pur-alpha. A complex between Tat and Pur-alpha acts to stimulate transcription at both the HIV-1 TAR RNA element and the JCV late promoter. The complex also interacts with T-antigen to enhance JCV DNA replication. Pur-alpha is a frequent partner of Cyclin/Cdk complexes, as is another Tat-binding protein, Cyclin T1.

       A major project involving lung cancer aims to elucidate the mechanism by which cells distinguish newly-replicated DNA, and its associated proteins, in S and G2 phases of the cell cycle and prevent that DNA from reinitiating replication in the same cycle. A primary hypothesis is that alterations in activity of an MCM4, 6, 7 helicase complex, necessary for initiation or reinitiation, are mediated by Cdk-dependent phosphorylation.  We are pursuing findings that Cyclin A/Cdk2 and sequence-specific single-stranded DNA-binding protein, Pur-alpha, are colocalized with once-replicated DNA in S and G2, that Pur-alpha modulates activity of Cdk2 and that Pur-alpha colocalizes with MCM7 on chromatin. We shall ascertain using chromatin immunoprecipitation (ChIP) and re-ChIP with successive antibodies the location and timing of assembly and dissociation of MCM4, 6 and 7 helicase components and the helicase inhibitor, MCM2, upstream of the c-MYC gene in the cell cycle of small-cell lung carcinoma cells and normal controls. We are examining whether Pur-alpha modulates the MCM4, 6, 7 helicase, either by association with Cyclin A/Cdk2 or by DNA unwinding. Results allow identification of links between control of initiation of replication and imposition of checkpoint controls that are critical in preventing progression to cancer.

       We are exploring the dynamics of the interactions between Tat, T-antigen and Pur-alpha during the course of JCV infection of oligodendrocytes and are determining whether transcriptional activation involves activity of Cyclin T1/Cdk9. We are detailing the mechanism by which Tat enhances replication initiated at the JCV origin in human oligodendrocytes both in vivo and using a new in vitro system. We are also examining the ability of TAT and Pur-alpha to interact with Smad effectors of the TGF-beta1 pathway. Results will help elucidate pathways of activation of HIV-1 and JCV in the brain and will help target particular molecular interactions for therapy.

       Our laboratory has generated five patents.

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