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Karolina Maciag, A Computational Approach to the Identification of Protein Network Elements Involved in the Coupling of Gene Expression Machines in Eukaryotic Cells, presented to the Department of Biochemical Sciences, Harvard University, 2004.
The objective of this project is to gain a better understanding of the mechanisms involved in the coupling of different steps of gene expression in yeast. The approach is to carry out a computational analysis of interactions between the molecular machines required for each step. While these steps (transcription initiation, elongation, termination, capping, splicing, polyadenylation, nonsense-mediated decay, and export) are known to be functionally and physically coupled, the mechanisms by which they are linked are poorly understood. Here I describe a novel method for the systematic discovery of key players in this coupling through the reconstruction and analysis of protein interaction networks. A comprehensive, weighted network of interacting proteins involved in processes of gene expression was assembled from diverse sources of available data including physical verification and computational inference and prediction. The protein network was partitioned into clusters corresponding to structural and functional modules, and putative coupling links were identified in the graph. The list of potential couplers thus generated provides a set of hypotheses that can be subjected to experimental validation. Furthermore, the functional modules identified suggest functions for previously uncharacterized complexes and individual protein products.