A computational investigation of the formation and structure of DNA intrastrand cross-links initiated by the uracil radical

Using computational methods, the formation pathways and structures of four experimentally-observed DNA intrastrand cross-links are determined. These lesions originate from the uracil radical and are of particular importance due to their potential role in the activity of the 5-halouracils as radiosensitizing agents in anti-tumour treatments. The formation pathways are studied with density functional theory under conditions relevant to both UV and ionizing radiation. Results reveal these intrastrand cross-links are likely to form under therapeutic conditions and provide an explanation for their observed formation preferences. The structures of the cross-links in DNA are determined with molecular dynamics simulations to reveal the distortions these lesions induce to the helix. This has provided information about the potential biological implications of these lesions, where results indicate intrastrand cross-links are likely both mutagenic and cytotoxic. Therefore, these lesions may contribute to tumour cell death in the therapeutic use of halouracils.

Author

• Churchill, Cassandra D.M

• Uracil -- Research
• Free radicals (Chemistry) -- Therapeutic use -- Research
• DNA damage -- Research
• Density functionals
• Dissertations, Academic

Identifier

hdl:10133/3117

OAI identifier oai:identifier

oai:opus.uleth.ca:10133/3117