3-(2-Deoxy-ß-D-erythro-pentofuranosyl)pyrimido[1,2-∂]purin-10(3H)-one (M1dG) is an exocyclic lesion produced endogenously by lipid peroxidation product malondialdehyde and DNA backbone oxidation products base propenals. It can undergo further oxidation in vivo to form 3-(2-Deoxy-β-D-erythropentofuranosyl)-pyrimido[1,2-f]purine-6,10(3H,5H)-dione (6-oxo-M1dG). Here, Here, we present melting temperature data and experimentally determined structure of the 6-oxo-M1dG DNA duplex by NMR spectroscopy which give insight into structural effects of 6-oxo-M1dG incorporation into the oligodeoxynucleotide 5'-d(C1A2T3X4A5T6G7A8C9G10C11T12)-3':5'-d(A13G14C15G16T17C18A19T20C21A22T23G24)-3' (X = 6-oxo-M1dG). Melting temperature data show the incorporation of 6-oxo-M1dG reduces the thermal stability of DNA duplex. NMR spectroscopy reveal an ordered structure for the 6-oxo-M1dG DNA duplex and afford detailed spectroscopic resonance assignments. 2D NOESY spectra indicate that 6-oxo-M1dG disrupts NOEs between 6-oxo-M1dG and A5, as well as NOEs between T20 and C21, base pairing neighbor of 6-oxo-M1dG. 2D COSY and NOESY spectra both show C21 is deshielded in the 6-oxo-M1dG duplex. 2D COSY data indicate there may be a minor conformation of 6-oxo-M1dG at low temperature. Structural refinement, using molecular dynamics calculations restrained by NOE data (rMD), revealed the structure of the 6-oxo-M1dG DNA duplex. 6-oxo-M1dG disrupted the DNA structure by kicking the C21 out of the helix toward major groove, it also and interupting the base stacking of T20 and C21. The understanding of the structure of 6-oxo-M1dG lesion in DNA will assist the future studying of 6-oxo-M1dG repair process as well its mutagenicity to the cells.

Investigation of structrual effects of 6-oxo-M1dG lesion in DNA

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