Author ORCID Identifier
0000-0002-8503-9435
Date of Award
5-6-2024
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Chemistry
First Advisor
Ivaylo Ivanov
Second Advisor
Donald Hamelberg
Third Advisor
Kathryn Grant
Abstract
Genomic DNA endures constant damage from endogenous and exogenous sources. Therefore, DNA needs to be specifically repaired to ensure the integrity of the genome. Left unrepaired, DNA damage can cause human diseases, including cancers. Of all DNA repair pathways, nucleotide excision repair (NER) is the most versatile, recognizing a wide array of structurally unrelated helix distorting lesion. NER has two sub-pathways: global genomic NER (GG-NER), which takes place anywhere in the genome, and transcription-coupled NER (TC-NER), which occurs when RNA polymerase II (pol II) encounters DNA damage during transcription. While the repair processes are essential for life, the mechanisms of DNA repair are still not completely understood. To shed light on the mechanisms of NER, we built structural models of key GG-NER (e.g., the pre-incision complex) and TC-NER complexes (Pol II/CSB/DNA) and carried out extensive molecular dynamics simulations to uncover their functional dynamics. Specifically, we address the role of the CSB protein in the transcriptional bypass of non-bulky DNA lesions by RNA polymerase II, the lesion scanning mechanism of transcription factor IIH in GG-NER, and the role of the pre-incision complex in licensing the dual incision by the XPG and XPF nucleases in GG-NER. Collectively, our results not only improve fundamental understanding of NER mechanisms but also shed light on the etiology of devastating human genetic disorders – xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome.
DOI
https://doi.org/10.57709/36967228
Recommended Citation
Yu, Jina, "Molecular Modeling of the Complex Protein Machinery of Nucleotide Excision Repair." Dissertation, Georgia State University, 2024.
doi: https://doi.org/10.57709/36967228
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