We have utilized NMR to delineate the chemistry and biology of complex DNA damage arising subsequent to N7-alkylation of dG by environmental mutagens and chemotherapeutic agents. One manner in which N7-dG adducts rearrange is to form N6-(2-Deoxy-D-erythro-pentofuranoysl-)-2,6-diamino-3,4-dihydro-4-oxo-5-N-alkylformamidopyrimidine (AlkylFapy-dG). Using NMR, we probed the equilibrium chemistry of the Me-Fapy-dG and the AFB1-Fapy-dG adducts in DNA. These lesions equilibrate between α or β anomers, and for each anomer, atropisomerism may occur around the MeFapy-dG C5-N5 bond to produce Ra and Sa atropisomers. Each atropisomer also exhibits geometrical isomerism about the MeFapy-dG formyl bond yielding E and Z conformations. The relative abundances of these species have been determined in single strand and duplex DNA. These may be differentially recognized during DNA processing, providing a mechanistic basis for the generation of sequence-specific repair and replication processing. Initially formed N7-dG adducts also depurinate to form apurinic sites (AP sites) in DNA. AP sites, once formed, epimerize via a reactive aldehyde intermediate, which may conjugate with anthracycline anti-tumor agents such as doxorubicin, or form DNA interstrand cross-links (ICL), both of which are potential cytotoxic endpoints. Progress in utilizing NMR to examine the chemistry and biology of AP sites, including an ICL involving the conjugation of AP sites with the N6-dA in the complementary DNA strand will be presented.

Probing chemical biology of DNA damage using NMR

2019 Fall National Meeting

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