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Gene Regulation and Signaling

Regulation of gene expression is an intricate process involving DNA replication, transcription and translation. Central to each step in this tightly controlled net of operations are assemblies between nucleic acids and proteins. Likewise, signaling events within the cell involve an elaborate interplay between proteins undergoing specific modifications, used as “on/off” switches. Our laboratory has used a combination of approaches to physically map and biophysically and structurally characterize these interactions.

In simple, prototypic systems such as viruses, proteins necessary for replication are responsible for recognition of the origin sequences, unwinding of the nucleic acid, and initiation of replication. We have investigated rolling circle replication, the paradigm for autonomously replicating nucleic acid elements, and have structurally elucidated essential components of the replisome, such as the Rep protein. In addition protein-protein signaling involving phosphorylation is another area of special focus.

At present we are investigating a multi-component regulatory hub controlling the nutrient-sensing enzyme SIRT1. This protein lies at the crossroads of a complex array of molecular interactions that impact susceptibility to diseases as diverse as obesity, diabetes, and others. SIRT1 activation results in increased expression of catabolic PGC-1alpha/PPARalpha target genes that help to protect against diet-induced obesity. We are studying the structural basis for the regulation of SIRT1 deacetylase activity, mediated by multifaceted communications through a PACS-2, DBC1 and SIRT1 tripartite center.