Sebastian Fica

Most mammalian genes are transcribed into precursor messenger RNAs (pre-mRNAs), from which non-coding introns are spliced out in the nucleus before the mRNA is exported to the cytoplasm and translated into proteins. Introns expand proteomic diversity by allowing a single gene to encode multiple mRNA isoforms and thus multiple protein isoforms with distinct activities. Splicing is performed by the spliceosome – a dynamic assembly of RNA and proteins and splicing errors are implicated in up to 30% of human diseases. Many proteins influence the conformation of the spliceosome and regulate alternative splicing to produce multiple mRNA isoforms from individual pre-mRNAs. We use electron cryomicroscopy, biochemistry, and sequencing to understand in molecular detail how splicing proteins modulate spliceosome dynamics to ensure correct splicing of different pre-mRNAs. We are excited to explore the possibility that alternative splicing, normally studied during initial spliceosome assembly, may also be regulated during splicing catalysis. We hope these studies will reveal fundamental insights into how alternative splicing is regulated in specific tissues and developmental states and will uncover novel splicing factors and potential therapeutic targets.