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Title: mRNA export and cancer
Author: Cumberbatch, Marcus G.
ISNI:       0000 0004 5992 9543
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2016
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Bladder cancer (BC) is the fourth commonest male malignancy worldwide and one of the most expensive to manage. The two greatest risk factors are tobacco smoking and occupational carcinogen exposure. In chapters 3 and 4, I contemporize the landscape of two leading causes for BC via a systematic review and meta-analysis of the published literature. I find that current smokers (versus ex-smokers or non-smokers) and those in tobacco, dye and factory industries have the greatest BC incidence. Carcinogenesis is the result of many molecular interactions and pathways that are not completely understood. Changes to RNA processing and transport are known to play a role in cancer biology. Transport of mRNA from the nucleus to the cytoplasm is essential for eukaryotic gene expression. ALYREF is central to the major mRNA export pathway involving the TREX complex; however, it is frequently down-regulated in high grade tumours. In chapter 5, we show that a previously uncharacterized cancer testis antigen LUZP4 defines a novel mRNA export pathway up-regulated in cancer. Post-translational modifications provide another level of gene expression control. In chapter 6, we show that poly (ADP-ribosyl)ation results in a global mRNA export block and alters TREX assembly by modifying the interaction between ALYREF and the RNA helicase UAP56 upon DNA damage. We show for the first time that PAR can bind UAP56 and identify the specific binding site. By advancing our knowledge of the LUZP4 mRNA export pathway and the effects of poly (ADP-ribosyl)ation on mRNA export we identify possible future targets for manipulation as biomarkers or therapeutic avenues.
Supervisor: Wilson, Stuart A. ; Catto, James W. F. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available