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Download StatisticsEaton, Charlotte (2019). Characterisation and regulation of a novel Lysyl Hydroxylase, JMJD7. University of Birmingham. Ph.D.
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Eaton2019PhD.pdf
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Abstract
Post-translational modifications (PTMs) are found throughout cell biology and are essential for normal cell growth and survival. Hydroxylation is a PTM that is generally catalysed by a family of enzymes known as 2-oxoglutarate (2OG) oxygenases. A sub-family of 2OG oxygenases with a ‘Jumonji-C’ (JmjC) catalytic domain have important regulatory functions in gene expression control and are often deregulated in disease. However, within this family of enzymes there remain a number of uncharacterised “orphan” enzymes, whose substrates remain unknown and potential roles in disease is not yet investigated. One of these orphan enzymes is Jumonji-C Domain 7 (JMJD7). Here, we contribute to the first biochemical characterisation of JMJD7, which is an active 2OG oxygenase with lysyl hydroxylase activity towards the Developmentally Regulated GTP binding Proteins, DRG1 and DRG2. Furthermore, we investigate a role for JMJD7 and pathway components in cancer, with our findings indicating potential tumour suppressive functions, including in gastric cancer. Cancer mutation analysis identified “hot-spots” within the JMJD7 gene which may be of functional importance. One cancer mutation hot-spot centres around a conserved N-terminal threonine phosphorylation site, indicative of a potential novel regulatory domain. However, the role of phosphorylation in regulating JMJD7 function and the kinase responsible for this modification were not known. Our work demonstrates that JMJD7 phosphorylation contributes to its role in growth, is cell cycle regulated, and may be catalysed by a cyclin-dependent kinase. Finally, we discuss the outcomes in the wider context and look towards the future directions of this project.
| Type of Work: | Thesis (Doctorates > Ph.D.) | |||||||||
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| Award Type: | Doctorates > Ph.D. | |||||||||
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| Licence: | All rights reserved | |||||||||
| College/Faculty: | Colleges (former) > College of Medical & Dental Sciences | |||||||||
| School or Department: | Institute of Cancer and Genomic Sciences | |||||||||
| Funders: | Other | |||||||||
| Other Funders: | University of Birmingham, AE Hills Scholarship | |||||||||
| URI: | http://etheses.bham.ac.uk/id/eprint/9507 |
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