Turner, Abigail Lucy;
(2023)
An integrated approach to understanding RNA recognition by the protein Syncrip.
Doctoral thesis (Ph.D), UCL (Univeristy College London).
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Abstract
Syncrip is an RNA binding protein which plays a pivotal role in human neuronal development and in the regulation of the endogenous circadian clock. Unsurpris- ingly, dysregulation and malfunction of Syncrip are linked to numerous diseases, including intellectual disability, muscular dystrophies, and cancer. At the cellular level, Syncrip regulates multiple steps of RNA metabolism and translation. The diverse functions of Syncrip are underpinned by its ability to select distinct sets of RNA targets via its multiple RNA-binding domains. Syncrip is part of a growing group of RNA regulators, whose individual domains play a target dependent role in RNA recognition and thus can bind distinct sets of targets. This complexity of recognition makes it more challenging to understand Syncrip’s mechanism of RNA target selection. Notably, any information gained from Syncrip may help understand RNA target selection by other proteins of this class. Preliminary data indicated that the RNA-binding domains of Syncrip are likely to be in a dynamic relationship, which may be important to recognise dif- ferent sets of targets. To capture the range of possibilities, I utilised a bottom-up approach, starting with the individual domains, how they each bind RNA and how they interact with one another. Then, building on this foundation, I inves- tigated the binding of the four domains to Syncrip miRNA targets. Finally, I developed protein mutants which remove the RNA binding capabilities of indi- vidual domains, which will be used to interrogate cellular target recognition. Overall, this work has identified that RNA binding by NURR is not limited to the recently published Hexo motif on miRNA, but it can bind a broader range of RNA targets including on mRNA. Furthermore, NURR does not associate with the RRM domains in the apo protein, yet during binding to miRNA targets, the four domains come together to form an RNA binding surface.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | An integrated approach to understanding RNA recognition by the protein Syncrip |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2023. 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. |
| 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-pp.ucl.ac.uk/id/eprint/10176430 |
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