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Understanding the biological processes generating the mutational spectra observed in genomes

Nandi, Shuvro 2018. Understanding the biological processes generating the mutational spectra observed in genomes. PhD Thesis, Cardiff University.
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Abstract

Maintaining genome stability is essential for life. Since DNA is constantly exposed to the deleterious effects of both the internal and external cellular environment, mechanisms have evolved to sense and repair the consequent genetic damages within the chromatin environment. Repair of UV-induced DNA damage requires chromatin remodeling. How repair of this damage is organised and initiated remains largely unknown. Previous work demonstrated in yeast cells that Global Genome Nucleotide Excision Repair (GG-NER) in chromatin is organized into domains in relation to open reading frames. In this thesis, by examining DNA damage-induced changes in the linear structure of nucleosomes at these sites, I show how chromatin remodeling is initiated during GG-NER. In undamaged cells, I found that the GG-NER chromatin-remodeling complex occupies chromatin and establishes the nucleosome structure at genomic locations, now referred to as GG-NER complex binding sites (GCBS’s). These sites are frequently located at genomic boundaries that delineate chromosomally interacting domains (CIDs), which represent regions of higher-order nucleosome-nucleosome interaction. Repair in chromatin is initiated from these sites by the GG-NER complex-dependent disruption of dynamic nucleosomes that flank GCBS’s, demonstrating the importance of this mechanism to the efficient removal of DNA damage by NER. I then studied how this affects the pattern of mutations acquired in the genome, establishing a novel workflow to catalogue the acquired mutations in yeast cells treated with or without UV radiation. Additionally, the use of NMF for de novo extraction of mutational signatures from these mutational catalogues, successfully decomposed the biological processes of mutagen exposure and DNA repair deficiencies. I showed that the genomic features that are important for repair organisation determine the location and types of mutations within genome. These studies may explain how novel cancer genes involved in chromatin modification drive tumorigenesis.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Last Modified: 27 Mar 2019 10:56
URI: http://orca-mwe.cf.ac.uk/id/eprint/121160

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