Formamidopyrimidine (Fapy) lesions arise from N7-methylation of dG by chemotherapeutic agents such as temazolamide, forming N6-(2-Deoxy-D-erythro-pentofuranoysl-)-2,6-diamino-3,4-dihydro-4-oxo-5-N-methylformamidopyrimidine (MeFapy-dG). A 13C-MeFapy-dG lesion, in which the CH3 group of the MeFapy-dG was isotopically labeled with 13C, was incorporated into the trimer 5'-TXT-3' and the dodecamer 5'-C1 A2 T3 X4 A5 T6 G7 A8 C9 G10C11T12-3’ (X = 13C-MeFapy-dG). We probed the equilibrium chemistry of the MeFapy-dG lesion in DNA. Our studies reveal that the MeFapy-dG lesion exists in single strand DNA as ten configurationally and conformationally discrete species, eight of which may be unequivocally assigned. MeFapy-dG lesions undergo epimerization to produce either α or β anomers. In the trimer single strand DNA, for each deoxyribose anomer, atropisomerism occurs around the C5-N5 bond to produce Ra and Sa atropisomers. Each atropisomer also exhibits geometrical isomerism about the formyl bond yielding E and Z conformations. The relative abundances of these species have been determined. In duplex DNA, the MeFapy-dG lesion existed as six configurationally and conformationally discrete species. These species may be differentially recognized during repair and replication processing, providing a mechanistic basis for the generation of sequence-specific repair and replication events in damaged DNA.

Configurational and conformational equilibria of the N6-(2-Deoxy-D-erythro-pentofuranoysl-)-2,6-diamino-3,4-dihydro-4-oxo-5-N-methylformamidopyrimidine (MeFapy-dG) lesion in DNA

256th National Meeting (2018)

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