Dissertation
Investigating the effects of chromatin on rare and atypical UV lesion formation and chromatin remodeling for excision of UV damage
Washington State University
Doctor of Philosophy (PhD), Washington State University
2022
DOI:
https://doi.org/10.7273/000004992
Abstract
Ultraviolet (UV) light poses a constant threat to the genomic integrity of most terrestrial organisms, including humans. UV radiation forms helix-distorting lesions between neighboring pyrimidine bases, primarily cyclobutane pyrimidine dimers (CPDs) and pyrimidine-pyrimidone (6-4) photoproducts (6-4PPs). If left unrepaired, these lesions may result in mutations that promote skin carcinogenesis. The effects of this damage are compounded by the context in which the damage is occurring. The protein-DNA interactions seen within chromatin and transcription factor binding sites modulates both the formation and repair of UV-induced DNA damage. Additionally, chromatin remodelers influence the repair of this damage. In part one of this dissertation, we sought to determine how the less frequently formed 6-4PP is formed within chromatin, specifically within nucleosomes and DNA sequences frequently targeted by transcription factors. We found that 6-4PPs do not preferentially form in flexible linker DNA, but rather preferentially form within the rigid structure of DNA wrapped around a histone octamer. Specifically, we found 6-4PPs form more readily at positions within nucleosomes in which the minor groove of DNA faces out away from the histone octamer. We further found that binding by certain transcription factors orients DNA in a way that is favorable to 6-4PP formation, and this correlates to mutation hotspots seen in yeast. These studies highlight the unique interplay between chromatin structure and UV lesion formation. In part two of this dissertation, we sought to understand the influences of the SWI/SNF and RSC chromatin remodelers in the repair of UV-induced lesions. We found that the SWI/SNF remodeler is required for the efficient repair of a subset of genes, while the RSC remodeler is required for efficient lesion excision throughout the yeast genome. Further, RSC aids in the repair of CPD lesions within and near nucleosomes, and in both actively and inactively transcribed genes. The data presented here have improved our understanding of the influence of chromatin and its remodeling on UV damage formation and repair.
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Details
- Title
- Investigating the effects of chromatin on rare and atypical UV lesion formation and chromatin remodeling for excision of UV damage
- Creators
- Kaitlynne Alyse Bohm
- Contributors
- John J. Wyrick (Advisor)Steven Roberts (Committee Member)Lisa Gloss (Committee Member)William Davis (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Molecular Biosciences, School of
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 271
- Identifiers
- 99901019537801842
- Language
- English
- Resource Type
- Dissertation