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. First-principles 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 replication fork stalling that is implicated in early stage carcinogenesis.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.