Case Western Reserve University
Wood RT 100-8
10900 Euclid Avenue
Cleveland, OH 44106-4973
2004 Searle Scholar
The main focus of research in my lab is elucidating the structure and function of catalytic core of the spliceosome, the multi-mega Dalton ribonucleoprotein complex that performs splicing of mRNA precursors in eukaryotes. We take advantage of a novel, minimal spliceosome we have recently developed to learn about the function and evolution of the spliceosome. This minimal system, which catalyzes a reaction identical to the splicing reaction, consists of only two spliceosomal snRNAs. In addition to providing direct evidence for RNA catalysis in the spliceosome, and thus, settling the longstanding and central question of the identity of the catalytic domain, the minimal system provides a novel and powerful tool for studying the spliceosome. Since the minimal system bypasses the complicated spliceosomal assembly process, it offers the advantage of a simple, functional system that is amenable to manipulations not possible in the authentic spliceosome, and thus, provides the long-sought possibility of functional analysis of the spliceosomal catalytic core in isolation.Currently our studies on the minimal spliceosome follow three main lines of research. First, we use the minimal splicing system as a simple model of the catalytic domain of the spliceosome in order to characterize the biochemistry and mechanistic details of the splicing reaction. Next, the insights obtained from the minimal spliceosome will be used as a basis for understanding how splicing is performed in the authentic spliceosome. Specific conclusions obtained from the minimal system will be tested in the authentic spliceosome in order to obtain insight into the function of the catalytic core within its physiological context. Importantly, the minimal system provides a scaffold for analysis of the interactions and function of spliceosomal protein and RNP factors. By adding spliceosomal factors to the minimal system, we use biochemical methods to obtain high-resolution structural and functional information on their mode of interaction with the active site and with each other, and their effect on catalysis. Taken together, in addition to providing insight into the spliceosomal catalysis and evolutionary origin, the above studies may ultimately make it possible to build a more sophisticated minimal splicing system by inclusion of suitable spliceosomal factors, which in turn will provide a basis for further analysis of the organization and function of the authentic spliceosome.
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