Enhanced reactivity of the pyrimidine peroxyl radical towards the C–H bond in duplex DNA – a theoretical study

Abstract

The peroxyl radical exhibits a much stronger reactivity towards C1′–H1′ in duplex DNA with respect to single-stranded DNA.

Dynamics of 5R-Tg Base Flipping in DNA Duplexes Based on Simulations─Agreement with Experiments and Beyond

“…Approximately 400 Tg residues are formed in a normal cell each day, and 10–20% of genome damages have been attributed to the oxidative conversion of thymine to Tg. 12 − 18 Due to the chirality of the C5 and C6 atoms, Tg could exist as a mixture of the two pairs of cis - and trans - stereoisomers: the 5R cis–trans pair (5R,6S: 5R,6R) and the 5S cis–trans pair (5S,6R: 5S,6S). 19 − 21 The 5R-Tg stereoisomer is thought to be the more abundant of these, with an equilibrium ratio of 7:3 between cis -5R,6S and trans -5R,6R Tg in DNA oligomers containing the Tg·A base pair, while this ratio is 87:13% at the single-nucleoside level.…”

“…Thymine glycol (5,6-dihydro-5,6-dihydroxy thymine; Tg) is the most common oxidation product of thymine. Approximately 400 Tg residues are formed in a normal cell each day, and 10–20% of genome damages have been attributed to the oxidative conversion of thymine to Tg. − Due to the chirality of the C5 and C6 atoms, Tg could exist as a mixture of the two pairs of cis - and trans - stereoisomers: the 5R cis–trans pair (5R,6S: 5R,6R) and the 5S cis–trans pair (5S,6R: 5S,6S). − The 5R-Tg stereoisomer is thought to be the more abundant of these, with an equilibrium ratio of 7:3 between cis -5R,6S and trans -5R,6R Tg in DNA oligomers containing the Tg·A base pair, while this ratio is 87:13% at the single-nucleoside level. , The epimers are suggested to induce large structural changes to duplex DNA, reflected in the fact that the 5R-Tg base could be either extra-helical or coordinating to the opposing base on the complementary strand, depending strongly on the local interaction. , The exact form or distribution would thus be linked to gene translation. − Except for data from NMR spectra in solution in combination with 0.01 μs constrained molecular dynamics (rMD) simulations, reliable structural information related to Tg epimers is unfortunately not available. Although the Tg:adenine base pair is more biologically relevant, crystal structures are only available with cytosine opposite to 5R-Tg. , It was previously thought that mismatched or damaged bases had a certain chance of spontaneously flipping out of the double helix structure of a DNA molecule because they could not form a normal and stable Watson–Crick base pair interaction and that the flipped base would thus function as a signal to be recognized and captured by repair proteins. − This hypothesis lacks atomistic level evidence on the effect of particular Tg epimers on the DNA supramolecular structure in biologically relevant DNA.…”