Oxidative DNA damage contributes to cancer and degenerative diseases.  Guanine is particularly vulnerable to oxidation, creating guanine radicals which form crosslinks to proteins.  Here, we investigate the solvent isotope effect on oxidative DNA-protein crosslinking reactions for the oligonucleotide 5'-AATAXTTTTGTTTGCGTGGATGGTTCTC-3' (X = 2-aminopurine, a strong photooxidant).  For this oligonucleotide duplex, the amount of permanent guanine damage in the form of DNA-protein crosslinks depends on competition between back electron transfer from 2-aminopurine radical anion to the guanine radical cation and the trapping reaction, which may involve the formation of the neutral guanine radical.  Crosslinking experiments using this oligonucleotide with histone H2A yielded more damage in H2O than in D2O.  In contrast, in a flash-quench system where back electron transfer has been eliminated, D2O yielded more damage, consistent with greater yields of guanine radical in D2O.  Taken together, these results suggest that trapping involves the deprotonation of the guanine cation radical.

Solvent isotope effects on DNA-protein crosslinking

245th National Meeting (2013)

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