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Title: The effect of oxidative DNA lesions on transcriptional elongation by human mitochondrial RNA polymerase
Author: Miles, Sarah
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2013
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Accumulation of DNA damage within the mitochondria is associated with many age-related diseases, including neurodegenerative diseases. DNA lesions, particularly oxidative lesions, are known to increase within the nuclear and mitochondrial genomes with age. Whilst replication past DNA lesions might lead to mutations within the mitochondrial genome, and thereby mitochondrial dysfunction, DNA lesions can also be deleterious through disruption of transcription. Lesions that cause transcription to terminate prematurely may lead to the production of truncated proteins, or the loss of protein production. DNA lesions that do not halt transcription can be mis-coding, and lead to transcriptional mutagenesis. This could lead to production of proteins with an altered structure or function, and thereby lead to mitochondrial dysfunction. Prior to the commencement of this project there was no data on the effect of DNA lesions on transcription by the mitochondrial RNA polymerase. I aimed to study transcription by the human mitochondrial RNA polymerase (POLRMT) in the presence of DNA damage. The location of the mitochondrial genome within the mitochondrial matrix means it in close proximity to the highest source of reactive oxygen species within the cell. I therefore primarily focused on one of the most common oxidative DNA lesions, 8-oxoguanine (80G). The results reported in this project show that transcription by POLRMT is disrupted by 80G lesions, but that they can be bypassed, and when bypassed they have the potential for causing transcriptional mutagenesis. I demonstrated that 80G bypass is more efficient under more physiological conditions (in the presence of transcription factors) and that location of the 80G lesion further from the promoter also renders bypass more efficient. I also report steps made towards the real-time observation of transcription with the mitochondrial machinery in a single-molecule magnetic tweezers set up.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available