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Title: Clinically relevant MRE11 variants in bladder cancer
Author: Jevons, Sarah J.
ISNI:       0000 0004 6352 8574
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2015
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Personalised medicine aims to empower patients and clinicians to make informed choices in order to enhance treatment outcomes. Currently, muscle-invasive bladder cancer (MIBC) is treated with cystectomy or radiotherapy/chemoradiation with no clear survival advantage for either option. Identification of predictive biomarkers could facilitate choice between treatments and potentially improve overall survival rates. MRE11 is a damage signaling protein whose function is crucial for in the DNA damage response. Intriguingly, expression of MRE11 by immunohistochemistry (IHC) is a promising predictive biomarker of radiotherapy response in MIBC patients. Paradoxically in terms of DNA repair, patients with low expression of MRE11, have a significantly worse survival rate following radiotherapy than those expressing high levels of MRE11 (Choudhury et al. 2010; Laurberg et al. 2012). The aim of the project was to investigate the underlying mechanisms of MRE11 expression in bladder cancer. A novel C-terminally truncated MRE11 variant was detected in bladder cancer cell lines and patient samples. The variant was the result of a post-translational cleavage of wild type MRE11 by caspase activity. Although caspases were responsible for the cleavage of MRE11, expression of the variant did not increase following the induction of apoptosis, implying that non-apoptotic caspases were involved. The variant was found to be less stable than wild type MRE11 and degraded by the proteasome. Functional aspects of the variant were investigated and it was found that the variant was located in the nucleus, can complex with NBS1 and RAD50 and co-localised with yH2AX at double-strand break sites. However, expression of the truncated variant led to a reduction in the efficiency of homologous recombination. The truncated variant is therefore likely to have a functional impact on DNA repair, potentially in a dominant negative manner. This might explain why high MRE11 expression was associated with increased survival following radiotherapy in bladder cancer patients. The high expression of MRE11 could include detection of high levels of the variant, associated with defective DNA repair and hence increased radiosensitivity. An underlying mechanistic explanation further supports the use of MRE11 immunohistochemistry as a predictive biomarker. These findings could also contribute towards the development of novel treatment strategies for patients with bladder cancer.
Supervisor: Kiltie, Anne ; McGrowder, Eva Sponsor: Medical Research Council ; Cancer Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available