RNA degradation is a critical pathway that regulates homeostasis in all living organisms. In particular, it plays an important role in the control of cell proliferation. Indeed, the absence of the cytoplasmic 3’-5’ exoribonuclease Dis3L2 in humans can cause fatal foetal gigantism (Perlman syndrome) and can be a precursor to Wilms’ tumour in the kidneys. In Drosophila melanogaster, deletion of Dis3L2 results in larger wings and their precursor wing imaginal discs (WIDs), confirming its role in cell proliferation. In contrast, deletion of Pacman (XRN1), the only cytoplasmic 5’-3’ exoribonuclease, results in an increase in apoptosis and smaller WIDs. These results suggest that together, these two exoribonucleases control cell proliferation, most likely through RNA degradation. Finally, several microRNAs are known to have critical roles in cell proliferation. Through genome-wide and single-gene experiments, the aim of this thesis was to understand how Pacman and Dis3L2 control cell proliferation through the degradation of specific microRNAs in WIDs. small RNA sequencing experiments in pcm and dis3L2 null WIDs identified potential snoRNA and miRNA direct targets of Pcm and Dis3L2 and their isoforms. Several transcripts were examined further to determine their direct degradation by the enzymes and their functional impact in the mutant WIDs. Finally, the regulation of the miRNA cluster lncRNA:let7C in pcm null WIDs was explored.
|Date of Award||Jan 2022|
|Supervisor||Sarah Newbury (Supervisor)|