Abstract
Pyrimidine cyclobutane dimers are hazardous DNA lesions formed upon exposure of DNA to UV light, which can be repaired through oxidative electron transfer (ET). Laser flash photolysis and computational studies were performed to explore the role of configuration and constitution at the cyclobutane ring on the oxidative repair process, using the nitrate radical (NO3•) as oxidant. The rate coefficients of 8–280 × 107 M−1 s−1 in acetonitrile revealed a very high reactivity of the cyclobutane dimers of N,N’-dimethylated uracil (DMU), thymine (DMT), and 6-methyluracil (DMU6-Me) towards NO3•, which likely proceeds via ET at N(1) as a major pathway. The overall rate of NO3• consumption was determined by (i) the redox potential, which was lower for the syn- than for the anti-configured dimers, and (ii) the accessibility of the reaction site for NO3•. In the trans dimers, both N(1) atoms could be approached from above and below the molecular plane, whereas in the cis dimers, only the convex side was readily accessible for NO3•. The higher reactivity of the DMT dimers compared with isomeric DMU dimers was due to the electron-donating methyl groups on the cyclobutane ring, which increased their susceptibility to oxidation. On the other hand, the approach of NO3• to the dimers of DMU6-Me was hindered by the methyl substituents adjacent to N(1), making these dimers the least reactive in this series.
Highlights
Exposure to UV light from the sun (λ = 180–400 nm) causes hazardous DNA lesions in the human body, which can lead to melanoma, basal cell, and squamous cell skin cancer [1]
The higher reactivity of the DMT dimers compared with isomeric dimethylated uracil (DMU) dimers was due to the electron-donating methyl groups on the cyclobutane ring, which increased their susceptibility to oxidation
Cytosine forms the same type of dimers as thymine, but deamination occurs within only a few hours to yield the highly mutagenic uracil dimer [3]
Summary
The primary photo adducts implicated in skin cancer are pyrimidine cyclobutane dimers, which are formed through [2 + 2]. 25%) proceeds through [2 + 2] photocycloaddition between the alkene and carbonyl moiety to give an oxetane intermediate that undergoes ring-opening to the 6–4 adduct (Scheme 1, path B) [2]. Pyrimidine cyclobutane dimers can exist in four isomeric structures with head-to-head (syn, s), head-to-tail (anti, a), as well as cis (c) and trans (t) configuration at the cyclobutane ring. Because of geometrical constraints, only the cis,syn dimer is formed in DNA [4]. Such pyrimidine dimers can prevent DNA polymerases from transcribing DNA, thereby promoting the accumulation of errors [5]
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