VIRAL TRANSACTIVATION

Cold Spring Harbor Laboratory, Cold Spg Hbr NY

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Abstract

The overall goal of this project is to understand how association among viral and cellular transactivators can alter patterns of transcriptional regulation. We study how the activities of the cellular POU-homeo-domain transcription factor Oct-1 are modified by association with viral and cellular co-regulators, principally the herpes simplex virus (HSV) transactivator VP16. VP16 (also referred to as Vmw65 and aTIF) is a virion protein that upon HSV infection is released into the cell and activates transcription of the HSV immediate early (IE) genes by directing formation of a multiprotein-DNA complex---the VP16-induced complex----with Oct- 1 and a second cellular factor called HCF. Upon entry into the cell, VP16 first associated with HCF (also referred to as C1, VCAF, and CFF) independently of DNA, and then associates with the DNA- binding domain of Oct-1, a POU domain, on the cis-regulatory target of VP16 activation, the IE promoter-specific TAATGARAT (where R = purine) motif. Oct-1 also associates with a cell-specific co- regulator call OCA-B (also referred to as OBF-1 and Bob1) and an snRNA-specific basal regulatory complex call SNAPc or PTF. In this project, we will study how co-regulators associate with the Oct-1 POU domain and modify the activity of Oct-1, placing particular emphasis on the structure and function of the VP16 -induced complex. We will (I) analyze the three-dimensional structure of the VP16-induced complex; (ii) characterize Oct-1 POU- domain interactions with DNA and the viral co-regulator VP16; (iii) determine the mechanisms by which VP16 directs formation of the VP16-induced complex; (iv) elucidate the role of HCF in stabilization of the VP16-induced complex; and (v) characterize Oct- 1 POU-domain interactions with the cellular co-regulator OCA-B and the basal regulatory complex SNAPc.