HCMV IE72 CONTROL OVER NUCLEAR ARCHITECTURE

Roswell Park Cancer Institute Corp, Buffalo NY

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Abstract

DESCRIPTION (provided by applicant): The HCMV major immediate-early gene products, IE1 (IE72) and IE2 (IE86), colocalize with the major structural components, PML and Sp100, in subnuclear domains (PODs). IE72 alone mediates the loss of SUMO-l-modified PMI and Sp100, correlating with POD disruption. We have established that 1) IE72 is a viral kinase, 2) PML and IE86 are substrates for IE72, 3) IE72 kinase-activity correlates with loss of SUMO-modified PML and Spl00, and 4) IE72 kinase-activity correlates with POD disruption. We hypothesize that IE72 phosphorylates Spl00 thereby mediating loss of SUMO-modified Spl00 and facilitating POD disruption. It is likely that IE72-induced post-translational modifications of PML and IE86 as well as IE72-mediated POD disruption have profound effects on gene regulatory functions. Therefore, we propose to study these IE72-induced effects on PML-mediated gene expression and on the synergistic regulation of gene expression between the HCMV IE proteins. Strengths of the proposed investigation include an abundance of expression systems for IE72, access to ample supplies and equipment as well as mentor support through two highly successful senior investigators.