Loading...
Mechanistic Basis of Oxidative and UV-Induced Mutagenesis Revealed by Topological and Genetic Dissection of Lesion Formation and Repair
Cordero, Cameron B.
Cordero, Cameron B.
Citations
Altmetric:
License
License
DOI
Abstract
This dissertation investigates how DNA topology and chromatin structure influence the formation and mutagenic processing of ultraviolet and oxidative DNA lesions. The first study examines ultraviolet-induced mutagenesis and shows that single-stranded DNA regions exhibit heightened photochemical reactivity, forming noncanonical photoproducts beyond cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs). These lesions broaden the mutational spectrum to include contexts matching recurrent oncogenic substitutions such as BRAF V600E. The second study, published as Cordero et al. 2024, expands our understanding of how 8-oxo-7,8-dihydroguanine (8-oxoG) becomes mutagenic, finding multiple mechanisms for SNV mutations and detection of novel oxidation-induced deletion mutations. Genome-wide analyses showed that lesion formation and repair outcomes vary with chromatin organization, with mutations enriched at guanines facing inward toward the histone core, where base excision repair is less efficient. Additional evidence indicates that nucleotide excision repair, particularly transcription-coupled NER, also contributes to processing these oxidative lesions. Together, these studies establish that DNA structure and chromatin topology dictate lesion formation, repair pathway engagement, and mutational outcomes, providing a mechanistic framework for the structural origins of cancer-associated mutation signatures.
Description
Date
2026