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Non-canonical spliceosomal assembly and function

Faraway, Rupert; (2021) Non-canonical spliceosomal assembly and function. Doctoral thesis (Ph.D), UCL (Univeristy College London). Green open access

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The spliceosome is a core component of the cellular machinery, orchestrating the splicing reaction that is necessary for the expression of the vast majority of genes. The function of the spliceosome in splicing has been characterised at near-atomic resolution, but little is known about whether the spliceosome performs functions in addition to the canonical splicing reaction. In this thesis, I address this matter by using spliceosome iCLIP (individual nucleotide-resolution crosslinking and immunoprecipitation) to observe unexpected interactions between spliceosomal components and RNA. First, I identify spliceosomal binding sites in deep intronic space and determine that the spliceosome can fully assemble at cryptic intronic splice sites without progressing to splicing catalysis. These intronic sites appear to function as ‘decoy splice sites’, interfering with the canonical splicing of their host introns. Second, I identify post-transcriptional spliceosomal interactions with spliced mRNA that are unrelated to the splicing reaction. These interactions are highly concentrated in purine-rich stretches of RNA and co-occur with multiple other RNA binding proteins (RBPs). I present evidence that this assembly on spliced mRNA regulates RNA export to the cytoplasm and that it likely occurs within the nuclear speckle. I show that the purine-rich regions that recruit this assembly preferentially encode low complexity protein regions containing charged amino acids. I then extend this observation to present a hypothesis of how RBPs can recognise specific types of low complexity protein region at the RNA level through multivalent assembly on low complexity RNA sequences. In summary, I have extended our understanding of spliceosomal function and RNA biology.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Non-canonical spliceosomal assembly and function
Event: UCL
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
Keywords: Spliceosome, RNA
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10134574
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