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Title: Human ribosome biogenesis and the regulation of the tumour suppressor p53
Author: Pelava, Andria
ISNI:       0000 0004 6423 9416
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2017
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Ribosome production is an energetically expensive and, therefore, highly regulated process. Defects in ribosome biogenesis lead to genetic diseases called Ribosomopathies, such as Dyskeratosis Congenita (DC), and mutations in ribosomal proteins and ribosome biogenesis factors are linked to multiple types of cancer. During ribosome biogenesis, the ribosomal RNAs (rRNAs) are processed and modified, and defects in ribosome biogenesis lead to the activation of p53. This project aimed to investigate the functions of Dyskerin, mutated in X-linked DC, in human ribosome biogenesis and p53 regulation, and to explore the link between ribosome production and p53 homeostasis. Dyskerin is an rRNA pseudouridine synthase and required for telomere maintenance. There is some debate as to whether DC is the result of telomere maintenance or ribosome biogenesis defects. It is shown here that human Dyskerin is required for the production of both LSU and SSU, and knockdown of Dyskerin leads to p53 activation via inhibition of MDM2 via the 5S RNP, an LSU assembly intermediate which accumulates after ribosome biogenesis defects. My data indicate that p53 activation, due to defects in ribosome biogenesis, may contribute to the clinical symptoms seen in patients suffering with DC. In addition, it is shown that defects in early or late stages of SSU or LSU biogenesis, result in activation of p53 via the 5S RNP-MDM2 pathway, and that p53 is induced in less than 12 hours after ribosome biogenesis defects. SSU defects do not cause any obvious defects in LSU production, but they result in inhibition of export of the pre-LSU in the cytoplasm, suggesting that p53 activation after SSU defects is probably due to defects in pre-LSU export. Finally, there are evidence that RPS27a or RPL40, two ribosomal proteins produced as ubiquitin-fusion precursors in the cell, might be novel regulators of the 5S RNP-MDM2 pathway. In conclusion, this work shows the importance of ribosome biogenesis in the regulation of p53 for the development of Ribosomopathies and cancer.
Supervisor: Not available Sponsor: BBSRC ; Diamond-Blackfan Anaemia Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available