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.

Five selected publications with PhD students underlined:

Strittmatter, L. M., Capitanchick, C., Newman, A. J., Hallegger, M., Norman, C. M., Fica, S. M.*, Oubridge, C., Luscombe, N.*, Ule, J.*, Nagai, K. (2021) PsiCLIP reveals dynamic RNA binding by DEAH-box helicases before and after exon ligation. Nature Communications, 12, 1488. *corresponding authors

Wilkinson, M. E.*, Fica, S. M.*, Galej, Wojtek P. & Nagai, K. Structural basis for conformational equilibrium of the catalytic spliceosome. (2021) Molecular Cell, 81, 1-14. *corresponding authors

Fica, S. M.*, Oubridge, C., Wilkinson, M. E., Newman, A. J., Nagai, K.* (2019) A human postcatalytic spliceosome structure reveals essential roles of metazoan factors for exon ligation. Science, 363, 710-714, *corresponding authors.

Wilkinson, M. E., Fica, S. M., Galej, W. P., Norman, C. M., Newman, A. J., Nagai, K. (2017) Postcatalytic spliceosome structure reveals mechanism of 3'-splice site selection. Science, 358, 1283–1288.

Galej, W. P., Wilkinson, M. E., Fica, S. M., Oubridge, C., Newman, A. J., & Nagai, K. (2016). Cryo-EM structure of the spliceosome immediately after branching. Nature, 537, 197–201.