Understanding the molecular basis of Splicing Regulation

The majority of mammalian mRNAs contain introns, which need to be removed to ensure proper translation. In turn cells have evolved elaborate multiprotein-complexes that efficiently and accurately regulate their removal. Many of these proteins have RNA recognition motifs that enable RNA recognition. One of this, PTB is perhaps one of the most crucial splicing factors. We were the first to elucidate the basis for PTB-RNA recognition (Science, 2005) as well as of Fox-1 (EMBO J, 2006), SRSF1 (PNAS 2013) and SRSF2 (EMBO J, 2012). In total, we solved the structure of more than a dozen alternative-splicing factors bound to RNA. Most recently, we provided structural and functional evidence that explain how disease-associated alternative-splicing factors bind RNA i.e hnRNP A1 is critical for motor neuron viability (1), TDP-43 (2) and FUS (3) in Amyotrophic Lateral Sclerosis (ALS) and how small molecule drug can correct splicing defect (4) (see Fig. 1).

1- Beusch I, Barraud P, Moursy A, Cléry A, Allain FHT. (2017) “Tandem hnRNP A1 RNA recognition motifs act in concert to repress the splicing of survival motor neuron exon 7.” Elife. 2017 Jun 26;6. pii: e25736.

2. Lukavsky P., Daujotyte D., Tollervey J., Ule J., Stuani C., Buratti E., Baralle F., Damberger F.F., Allain F.H.T. (2013) “Molecular basis of UG-rich RNA recognition by the human splicing factor TDP-43” Nat. Struct. Mol. Biol. 20, 1443-9.

3- Loughlin F.E†, LukavskyP.J., Kazeeva T., Reber S, Hock E.-M, Colombo M., Von Schroetter C., Pauli P., Clery A., MühlemannO., PolymenidouM., Ruepp M.-D., Allain F.H.T. † (2018) “The solution structure of FUS bound to RNA reveals a bipartite mode of RNA recognition with both sequence and shape specificity.” Mol. Cell, 73(3):490-504.

4- Campagne, S. Boigner, S., Rüdisser, S., Moursy, A., Gillioz, L., Knörlein, A., Hall, J., Ratni, H., Cléry, A. and Allain, FHT. (2019), “'Structural basis of a small molecule targeting RNA for a specific splicing correction.” Nat. Chem. Biology, Dec;15(12):1191-1198.