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Genetics of Herpesvirus Transformation


Project Summary/Abstract The long-term goals of this research are to define 1) the mechanisms by which herpes simplex virus (HSV) remodels the host cell nucleus to optimize its replication and 2) the functions and mechanisms of action of the HSV infected cell protein 8 (ICP8) ssDNA binding protein. In this application our specific aims are to: 1. Define the mechanisms of chromatin regulation on viral DNA through targeting of the viral genome to the nuclear lamina in studies to determine the viral and host gene products needed for peripheral targeting of viral genome complexes and studies to determine the viral and host gene products that regulate heterochromatin levels on the viral genome. 2. Define the mechanisms of assembly and function of replication compartments by studies of the role of lamin A/C in the assembly and structure of replication compartments through identification of ICP8 domains required for interaction with lamin A/C, construction of mutant viruses defective for ICP8 interaction with lamin A/C, and phenotypic characterization of mutant viruses; and studies of the roles of chromatin-remodeling enzyme complexes and histone modification enzymes in viral replication by knockdown of expression of chromatin-remodeling proteins that are recruited to replication compartments, and studies of ICP8 and its effect on acetylation of histones on late gene promoters. 3. To define the mechanisms and function of replication compartment movement and nuclear lamina ruffling in HSV replication and remodeling of the host cell nucleus by quantitatively characterizing replication compartment movement, determining if replication compartment movement depends on ongoing viral replication and/or transcription, and by determining if nuclear actin and myosin or lamins are involved in replication compartment movement. These studies should provide important information about the mechanisms of remodeling of the host cell nucleus that HSV uses to optimize its replication, and the studies also have the potential to provide new insight into current issues in nuclear molecular processes, including the role of targeting of chromatin to the nuclear lamina and chromatin regulation, chromatin structure and transcriptional regulation, and chromosome movement and transcriptional activation. Each of these important cell biological problems will be investigated in this proposed research. New antiviral targets for inhibition of herpesviral replication may also be elucidated.

Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.