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Title: Mathematical model of 'on-demand' histone protein synthesis during S phase in humans
Author: Christopher, Andrea
ISNI:       0000 0004 5993 0632
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2016
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During DNA replication the DNA has to be unpacked, duplicated and repacked into chromatin, which is comprised of DNA and histone proteins (Nicholson and Muller, 2008b). The coordinated replication of DNA and histone protein synthesis is vital for the correct chromatin formation (Marzluff et al., 2008). The mechanism controlling the histone gene expression is only partially understood, especially the mechanism controlling any disturbances in the coordination of DNA replication and histone protein synthesis. Previous experiments suggested that the regulation mechanism of histone balance could involve regulation by a free histone protein pool (Takami and Nakayama, 1997b; Takami and Nakayama, 1997a; Dominski et al., 2005; Kroeger et al., 1995). A mathematical model was produced by Dr Hameister (Hameister, 2012) to describe the control of histone production during S phase. The parameters used were taken from literature. Modifications were made using experimentally measured data to replace literature values (Harris et al., 1991; Clark, 2006; Strachen and Read, 2003). The aim of the project was to both optimise the model by defining parameters to reflect what occurs naturally in the cell, as well as trying to validate the model. The DNA replication rate was measured by FACS analysis and was input into the model. Histone RNA levels during S phase were measured by Northern blots and histone RNA degradation rates were analysed. To confirm that the modified DNA replication rate was producing accurate simulations, the curve produced for the mRNA levels could be compared to the experimentally measured mRNA values (Figure 4.3.1). The over expression of an H2B gene was verified using Western and Northern analysis. The validation of the model that the histone gene balance was being regulated by a free histone pool was not absolutely confirmed. However, results seen in Figure 3.6.1, showed an increase in H2B RNA degradation in the sample with the additional gene due to the additional histone proteins. Further work is required for confirmation of the regulation mechanism.
Supervisor: Not available Sponsor: Scottish Informatics and Computer Science Alliance ; University of Aberdeen
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: DNA replication ; Histones