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The role of DICER cofactors in microRNA biogenesis and immune checkpoint regulation in cancer cells

Hawkins, Sophie (2019) The role of DICER cofactors in microRNA biogenesis and immune checkpoint regulation in cancer cells. MSc by research thesis, University of York.

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Abstract

MicroRNAs are intrinsic regulators of gene expression, apparent in all major cellular pathways from differentiation to apoptosis. By targeting complementary mRNA, microRNA can direct post-transcriptional downregulation of gene-expression and fine tune levels of protein expression. Disruption to microRNAs on a global or singular scale has been linked to many diseases and cancers due to reduced genetic regulation. The biogenesis pathway of microRNAs is well documented, however the functions of proteins such as the DICER co-factors TRBP and PACT are not yet fully understood. Within this project, these two proteins were investigated in the context of microRNA biogenesis, with exploration into novel links to cellular immunity, with a focus on the immune checkpoint PD-L1. It is known that PD-L1 is directly regulated by microRNAs and has also been shown to be upregulated during dsRNA stress. The roles of TRBP and PACT were scrutinized through transient protein knockdown, where the impact of their depletion on selected microRNAs and PD-L1 was assessed through RT-qPCR and western blot. Endogenous interaction of TRBP and PACT was discovered within three different human cancer cell lines, where concurrent depletion of these DICER co-factors resulted in disrupted biogenesis of selected ubiquitous microRNAs. Both TRBP and PACT function in microRNA biogenesis, and PACT was also identified as a possible influencer of PD-L1 expression. Potential cross talk between miRNA biogenesis and immunity is further discussed through association with Protein Kinase R (PKR).

Item Type: Thesis (MSc by research)
Academic Units: The University of York > Biology (York)
Depositing User: Miss Sophie Hawkins
Date Deposited: 04 Jun 2019 13:38
Last Modified: 04 Jun 2019 13:38
URI: http://etheses.whiterose.ac.uk/id/eprint/24073

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