Oxidatively generated damage to DNA at 5-methylcytosine mispairs.
Oxidatively generated damage to DNA has been implicated as causing mutations that lead to aging and disease. The one-electron oxidation of normal DNA leads to formation of a nucleobase radical cation that hops through the DNA until it is trapped irreversibly, primarily by reaction at guanine. It has been observed that 5-methylcytosine (C(m)) is a mutational "hot-spot". However, C(m) in a Watson-Crick base pair with G is not especially susceptible to oxidatively induced damage. Radical cation hopping is inhibited in duplexes that contain C-A or C-T mispairs, but no reaction is detected at cytosine. In contrast, we find that the one-electron oxidation of DNA that contains C(m)-A or C(m)-T mispairs results primarily in reaction at C(m) even in the presence of GG steps. The reaction at C(m) is attributed to proton coupled electron transfer, which provides a relatively low activation barrier path for reaction at 5-methylcytosine. This enhanced reactivity of C(m) in mispairs may contribute to the formation of mutational hot spots at C(m).
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, USA.
Joshy
J
Joseph
Gary B
GB
Schuster
D044503:5-Methylcytosine / Q000737:chemistry* / Q000378:metabolism; D000225:Adenine / Q000737:chemistry; D020137:Base Pair Mismatch; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004249:DNA Damage; D010084:Oxidation-Reduction; D013941:Thymine / Q000737:chemistry; D014466:Ultraviolet Rays
D044503:5-Methylcytosine; D004247:DNA; D000225:Adenine; D013941:Thymine