Photoinduced Damage to Cellular DNA: Direct and Photosensitized Reactions^†

Abstract

The survey focuses on recent aspects of photochemical reactions to cellular DNA that are implicated through the predominant formation of mostly bipyrimidine photoproducts in deleterious effects of human exposure to sunlight. Recent developments in analytical methods have allowed accurate and quantitative measurements of the main DNA photoproducts in cells and human skin. Highly mutagenic CC and CT bipyrimidine photoproducts, including cyclobutane pyrimidine dimers and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs) are generated in low yields with respect to TT and TC photoproducts. Another striking finding deals with the formation of Dewar valence isomers, the third class of bipyrimidine photoproducts that is accounted for by UVA-mediated isomerization of initially UVB generated 6-4PPs. Cyclobutadithymine (T< >T) has been unambiguously shown to be involved in the genotoxicity of UVA radiation. Thus, T< >T is formed in UVA-irradiated cellular DNA according to a direct excitation mechanism with a higher efficiency than oxidatively generated DNA damage that arises mostly through the Type II photosensitization mechanism. C<>C and C< >T are repaired at rates intermediate between those of T< >T and 6-4TT. Evidence has been also provided for the occurrence of photosensitized reactions mediated by exogenous agents that act either in an independent way or through photodynamic effects.

Assessment of the Potential Energy Hypersurfaces in Thymine within Multiconfigurational Theory: CASSCF vs. CASPT2

“…Insight into their photochemical pathways provides unique information to ascertain the effect of light irradiation on the cellular system and is tightly related to the ability possessed by the genetic material to dissipate the excess of energy gained upon absorption in a harmless manner. This feature, known as photostability [12,13], is ascribed to the ultrafast decay of the excited state population to the ground state in a non-radiative manner mediated by conical intersections (CIs) between the initially accessed bright 1 (ππ*) and the ground state, justifying the sub-ps deactivation registered experimentally [3] and explaining the reduced damage registered in DNA despite our constant UV-light exposure [14,15].…”

Influence of DNA Lesions on Polymerase-Mediated DNA Replication at Single-Molecule Resolution

“…Common classes of lesions are UV-induced base damage, DNA alkylation, including bulky adducts, such as those formed by aromatic amines or polycyclic aromatic hydrocarbons, oxidative damage, and abasic sites (Figure 1). DNA lesions resulting from UV-exposure include cyclobutane pyrimidine dimers (CPD) and 6,4 photodimers (Figure 1), 14 which are the result of two monomeric nucleobases that react to form TT, CC, or TC dimers. 15−18 Alkylation or bulky DNA adducts result from the covalent attachment of a chemical agent to the DNA nucleobase such as methylating agents like methylmethanesulfonate (MMS) 19 or N-methyl-N-nitrosourea (MNU), 20 the environmental pollutant benzo[a]pyrene (B[a]-P) 21−24 acetylaminofluorene, 25,26 or the fungal metabolite aflatoxin 27−29 that can contaminate food supplies.…”

Photochemistry of 1,3-Dicarbonyl Compounds: DNA Photodamage vs. Photoprotection

“…Excitation of the endogenous or exogenous photosensitizer can lead to a huge variety of photoproducts arising from processes such as energy transfer, electron transfer or production of reactive oxygen species (ROS) ( Figure 6). [43], [44] Nonetheless, cells are equipped with complex and sophisticated systems such as DNA repair, damage tolerance, cell cycle checkpoints, and cell death pathways, which work altogether to reduce the undesirable consequences of DNA damage.…”

“…[43] In humans, the UV-induced DNA damages are repaired by the excision of the damaged portion, followed by the resynthesis using the undamaged strand as template and final ligation. For instance, BER helps to excise small oxidized bases, strand breaks and abasic sites [4], [44], [45] and NER excises bulky photoproducts (CPDs and 6-4PPs).…”

“…Their formation involves the ππ* excited states; however, the scientific community is still debating the excited state involved in this reaction, whether a localized or delocalized singlet or the triplet state ( Figure 7A). [44] In naked and cellular DNA, four possible CPDs have been isolated, they correspond to the TT (T˂˃T), CT (C˂˃T), TC (T˂˃C) and CC (C˂˃C) bipyrimidine sequences. A large number of isomers can be produced in function of the orientation of the two nucleobases, the different conformation being cis, syn; trans, syn; trans, anti; cis, anti.…”