Abstract:
One-electron oxidation of A/T-rich DNA leads
to mutations at thymine. Experimental investigation of DNA
containing methyl-deuterated thymine reveals a large isotope
effect establishing that cleavage of this carbon−hydrogen bond
is involved in the rate-determining step of the reaction. Firstprinciples
quantum calculations reveal that the radical cation
(electron hole) generated by DNA oxidation, initially located
on adenines, localizes on thymine as the proton is lost from
the methyl group, demonstrating the role of proton-coupled
electron transfer (PCET) in thymine oxidation. Proton transport by structural diffusion along a segmented “water-wire”
culminates in proton solvation in the hydration environment, serving as an entropic reservoir that inhibits reversal of the PCET
process. These findings provide insight into mutations in A/T-rich DNA such as eplication fork stalling that is implicated in
early stage carcinogenesis.
