A synthetic nucleoside probe that discerns a DNA adduct from unmodified DNA.

Department of Medicinal Chemistry and The Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Journal of the American Chemical Society (Impact Factor: 10.68). 04/2007; 129(16):4882-3. DOI:10.1021/ja070688g
Source: PubMed
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    ABSTRACT: The 2'-deoxynucleoside containing the synthetic base 1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)-1H-perimidin-2(3H)-one] (dPer) recognizes in DNA the O(6)-benzyl-2'-deoxyguanosine nucleoside (O(6)-Bn-dG), formed by exposure to N-benzylmethylnitrosamine. Herein, we show how dPer distinguishes between O(6)-Bn-dG and dG in DNA. The structure of the modified Dickerson-Drew dodecamer (DDD) in which guanine at position G(4) has been replaced by O(6)-Bn-dG and cytosine C(9) has been replaced with dPer to form the modified O(6)-Bn-dG:dPer (DDD-XY) duplex [5'-d(C(1)G(2)C(3)X(4)A(5)A(6)T(7)T(8)Y(9)G(10)C(11)G(12))-3']2 (X = O(6)-Bn-dG, Y = dPer) reveals that dPer intercalates into the duplex and adopts the syn conformation about the glycosyl bond. This provides a binding pocket that allows the benzyl group of O(6)-Bn-dG to intercalate between Per and thymine of the 3'-neighbor A:T base pair. Nuclear magnetic resonance data suggest that a similar intercalative recognition mechanism applies in this sequence in solution. However, in solution, the benzyl ring of O(6)-Bn-dG undergoes rotation on the nuclear magnetic resonance time scale. In contrast, the structure of the modified DDD in which cytosine at position C(9) is replaced with dPer to form the dG:dPer (DDD-GY) [5'-d(C(1)G(2)C(3)G(4)A(5)A(6)T(7)T(8)Y(9)G(10)C(11)G(12))-3']2 duplex (Y = dPer) reveals that dPer adopts the anti conformation about the glycosyl bond and forms a less stable wobble pairing interaction with guanine.
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    ABSTRACT: Oligonucleotide hybridization probes containing nucleoside analogs offer a potential strategy for binding specific DNA sequences that bear pro-mutagenic O(6)-G alkylation adducts. To optimize O(6)-Me-G-targeting probes, an understanding of how base pairs with O(6)-Me-G are stabilized is needed. In this study, we compared the ability of O(6)-Me-G and G to hydrogen bond with three pyrimidine-like nucleobases (Z, 4-thio-U, and 3-deaza-C) bearing varied hydrogen bond donor and acceptor groups. We found that duplexes containing the pyrimidine analog nucleoside:G pairs were more thermodynamically stable than those containing pyrimidine analog nucleoside:O(6)-alkyl-G pairs. Thus, hydrogen bonding alone was not sufficient to impart selectivity to probes that target O(6)-G alkylation adducts in DNA.
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