Computational studies of interstrand crosslink formation in DNA

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Takyi, Nathania
University of Lethbridge. Faculty of Arts and Science
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Lethbridge, Alta. : University of Lethbridge, Dept. of Chemistry and Biochemistry
Interstrand crosslinks (ICLs) are toxic DNA lesions that can result in cell death if left unrepaired. ICLs can form following the reaction of natural DNA nucleobases with reactive chemical species generated during DNA repair. This thesis uses computational methods to investigate ICL formation resulting from the reaction of DNA repair intermediates with DNA nucleobases. Molecular dynamics (MD) simulations are used to provide an explanation for the effects of sequence context on the yield of ICLs that form following attempted repair of 1,N6-ethenoadenosine by alpha-ketoglutarate dependent dioxygenase homolog 2 (ALKBH2). Subsequently, an explanation for the preference of different Ap-derived ICLs is provided using density functional theory (DFT) calculations and MD simulations. Finally, the effect of sequence context on the dA-Ap ICL yield is investigated using MD simulations. Overall, this thesis uses molecular modelling approaches to rationalize how sequence context affects ICL yield and reveals the role of the structure of damaged DNA in ICL formation.
Damaged DNA , Interstrand crosslinks , ICL formation , Molecular modelling , DNA lesions