Prof. Jernej Ule - How do protein-RNA condensates form and contribute to disease?
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Mutations in many genes encoding RNA-binding proteins (RBPs) cause neurologic diseases, and especially the amyotrophic lateral sclerosis (ALS). These mutations tend to be located within intrinsically disordered regions (IDRs) of RBPs. To understand how these mutations act, we developed crosslinking and Immunoprecipitation (CLIP) to obtain transcriptome-wide maps of in vivo protein-RNA interactions. I will also describe our recent technical advances that helped us to use CLIP in a quantitative manner and to gain broader insights from analyses of public data. We developed an improved individual nucleotide resolution CLIP protocol (iiCLIP), which produces highly sensitive and specific data, and thus enables quantitative comparisons of interactions across conditions (Lee et al., 2021). Finally, I will exemplify how these advances helped with studies of mutations in the IDR of TDP-43, a protein that is a central factor in ALS and several other neurodegenerative diseases. CLIP enabled us to disentangle the principles driving the condensation of TDP-43 on cellular RNAs, which showed that the IDR selectively fine-tunes the RNA binding properties and functions of the protein (Hallegger et al., 2021). I'll also discuss how insights into the specificity of RBP condensation open new doors for understanding of protein-RNA complexes as mediators of signalling, disease and evolution.
Hallegger, M., Chakrabarti, A.M., Lee, F.C.Y., Lee, B.L., Amalietti, A.G., Odeh, H.M., Copley, K.E., Rubien, J.D., Portz, B., Kuret, K., et al. (2021). TDP-43 condensation properties specify its RNA-binding and regulatory repertoire. Cell 184, 4680–4696.e22.
Lee, F.C.Y., Chakrabarti, A.M., Hänel, H., Monzón-Casanova, E., Hallegger, M., Militti, C., Capraro, F., Sadée, C., Toolan-Kerr, P., Wilkins, O., et al. (2021). An improved iCLIP protocol. bioRxiv, doi.org/10.1101/2021.08.27.457890
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