UCSF

The spliceosome is one of the cells largest and important molecular machines and yet it remains as one the least understood systems. This is a result of many experimentally challenging features inherent to the biology of splicing. In addition to having the largest number of unique proteins and RNAs associated with one process, the spliceosome has a complex assembly process that is both conformationally and compositionally dynamic. Classical genetics, much of it done in the Guthrie lab, revealed which proteins and RNAs were required for the process of splicing, but the molecular details of their interactions is still relatively unknown. In the past 10 years new biochemical tools have been developed, such as smFRET and metal substitution studies, which have increased our abilities to probe the structure and activity of the spliceosome. These techniques and others outlined in this proposal will be the foundation for the next ten years of research on the spliceosome. I believe that through these efforts and building on recent breakthroughs, the molecular mechanism of pre-mRNA splicing will be determined. These are truly exciting times to be studying the spliceosome.