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Title: The roles of human ribosome biogenesis factors in pre-rRNA cleavage and p53 regulation
Author: Wells, Graeme
ISNI:       0000 0004 7961 1081
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2018
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Ribosome biogenesis is a complex process that is upregulated in many cancers and downregulated during differentiation. Mutations in genes encoding ribosome biogenesis factors are associated with genetic diseases called ribosomopathies. Three of the four ribosomal RNAs (rRNAs), including the 18S rRNA of the small subunit (SSU), released from a single precursor by endonucleolytic cleavages and exonucleolytic processing. Despite extensive research into yeast ribosome biogenesis, the enzymes catalysing several cleavages in 18S rRNA maturation remain unknown, and even less is known in humans. Defective human ribosome biogenesis leads to the activation of the tumour suppressor, p53 via the 5S RNP, a large subunit (LSU) assembly intermediate. Unexpectedly, defective SSU biogenesis also results in p53 induction and multiple proteins implicated in 18S rRNA processing are mutated in cancers. This project aimed to identify endonucleases functioning in human 18S rRNA maturation and investigate the link between SSU biogenesis and p53 regulation. The data presented here provides evidence that the PIN domain protein UTP24 is the endonuclease responsible for pre-rRNA cleavage at two sites in human 18S rRNA maturation and argues against a direct role for the RNA cyclase-like protein Rcl1/RCL1 in pre-rRNA cleavage in yeast and humans. Additionally, this work shows that an intact UTP23 PIN domain is essential for human pre-rRNA processing, suggesting it may play an enzymatic role in pre-rRNA cleavage. Depletion of UTP23 leads to p53 induction, while a UTP23 mutation associated with colorectal cancer affects pre-rRNA processing in vivo but does not result in activation of p53. Multiple ribosome biogenesis factors are frequently mutated in cancers, including the RNAbinding protein RRP5 which plays key roles in 18S rRNA maturation. Depletion of RRP5 results in 5S RNP-dependent p53 activation. Human cell lines stably expressing mutant forms of RRP5, based on mutants used in yeast studies, were generated which will allow for the characterisation of human RRP5.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available