Photochemical Formation of Cyclobutane Pyrimidine Dimers in DNA through Electron Transfer from a Flanking Base

Abstract

Electron transfer (ET) to a pyrimidine base from external moieties is a common step involved in the quenching or repair of the cyclobutane pyrimidine dimer (CPD). In contrast, we present a pathway that is initiated by an ET from a flanking guanine base to a pyrimidine base, leading to the formation of a CPD. We studied a T5mCG sequence with a methylated cytosine and our results demonstrate that the pathway involves the formation of an exciplex and intersystem crossings. This pathway also provides an explanation for why the mutational hot spots are correlated with the methylated CpG sequences, which has been a significant issue in cancer research.

Stabilization of the Triplet Biradical Intermediate of 5‐Methylcytosine Enhances Cyclobutane Pyrimidine Dimer (CPD) Formation in DNA

“…Although the above‐mentioned studies assumed that CPD enhancement by 5mC occurs in the singlet state, we examined the corresponding mechanism in the triplet manifold because the free energy profile toward CPD formation in the singlet state showed a slightly higher barrier for TmCG than TCG owing to the bulky methyl group of 5mC [8] . In that study, the CPD forming pathway we found was initiated from a dark CT state, but the pathway demonstrated here is initiated from bright ππ* excitation.…”

“…Starting from the T 1 minimum we reached, we carried out restrained optimizations, adding 5mC into the QM region. Here, the distance between the C6 atoms of 5mC and thymine base was used as a reaction coordinate (Figure 3 A) because the pathway leading to CPD in the triplet manifold is known to undergo a biradical intermediate ( 3 BR), which has a single covalent bond between the C6 atoms of the two constituting bases [8, 10, 22, 23] . During these restrained optimizations, we observed a surface crossing between T 1 and the ground state, so we used linear response coupled cluster method of second order (CC2) [14] with def2‐SVP instead of ADC(2)/def2‐SVP for these optimizations because, although ADC(2) more correctly describes surface crossings between excited states, CC2 displays superior performance in describing surface crossings between the ground and excited state than ADC(2) [15, 16] .…”

“…In addition, C5‐methylation was also suggested to facilitate energy transfer from non‐reactive pyrimidines to reactive ones by increasing duplex rigidity [24] . However, other studies show a negligible effect of methylation on the conformation of oligonucleotides, which could affect reactivity [8] …”

“…These mechanisms involve singlet states. In addition, mechanisms involving triplet states accessed through intersystem crossing (ISC) have been proposed [7–10] . A recent study employing time‐resolved UV pump IR probe spectroscopy to examine the triplet‐induced CPD formation in dinucleotides CpT and TpC showed that the CPD formation is initiated by the localization of the triplet state in the constituting thymine base [11] .…”

Photoinduced DNA Lesions in Dormant Bacteria: The Peculiar Route Leading to Spore Photoproducts Characterized by Multiscale Molecular Dynamics**

“…In the future, we plan to study the whole SPP formation process and quantitatively establish the free energy penalty for CPD formation in the spore environment. Moreover, the possible influence of charge‐transfer states involving flanking nucleobases on the SPP formation remain to be studied [51–54] …”