Moss, CF;
(2018)
Persistent Ribonucleotides and Mitochondrial DNA Metabolism (in Normal and Disease States).
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
It has been known for over 40 years that the mammalian mitochondrial genome contains persistent sporadic ribonucleotides, for which there has been no molecular explanation to date. To better understand the significance of incorporated ribonucleotides in mitochondrial DNA I developed a deep sequencing method to determine the precise location of ribonucleotides in the mitochondrial DNA of a range of cell and tissue types. Using Next Generation Sequencing I have shown that the vast majority of ribosubstitution events in murine mitochondrial DNA from solid tissues are dominated by adenosine bases derived from adenosine triphosphate, the product of oxidative phosphorylation. In contrast, proliferating cells show a much lower rate of ribonucleotide incorporation. However, this can be manipulated by inducing cell cycle arrest, which leads to an increase in adenosine monophosphate incorporation rate, comparable to that of solid tissues. This study confirms that the specificity of the incorporated ribonucleotide base identity is directly influenced by the ratio of ribonucleotides to deoxyribonucleotides (NTP:dNTPs) within the mitochondrial compartment of the cell. In a mouse model of Mpv17 deficiency there is a mitochondrial specific deoxynucleotide depletion which results in a significant increase in riboguanosine incorporation in mitochondrial DNA. The results described within this thesis demonstrate that elevated riboguanosine incorporation is associated with early-onset mitochondrial DNA depletion in liver and late-onset multiple deletions in brain of the Mpv17 ablated mice. These findings suggest that aberrant ribonucleotide incorporation is a primary mitochondrial DNA abnormality that can result in pathology.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Persistent Ribonucleotides and Mitochondrial DNA Metabolism (in Normal and Disease States). |
| Event: | UCL |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| UCL classification: | UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10041696 |
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