Noncanonical Stacking Geometries of Nucleobases as a Preferred Target for Solar Radiation

Рамазанов, Р. Р.; Maksimov, Dmitrii; Kononov, Alexei I.

doi:10.1021/jacs.5b05140

Cited by 14 publications

(16 citation statements)

References 82 publications

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“…They coincided with binding sites of several sequence-specific transcription factors, which apparently make the DNA more susceptible to dimer formation by introducing a favorable structural distortion into the DNA double helix. Indeed, stacked dimers with reduced inter-base distances can form with lower energy excitation transitions in curved and highly distorted DNA structures (Ramazanov et al 2015). In contrast to these damage hotspots, other transcription factor-bound sites sustained much less CPD or (6-4)PP damage in cells compared to naked DNA, presumably because the bound factors were associated with a more rigid DNA structure that is incompatible with dimerization of the adjacent DNA bases (Tornaletti and Pfeifer 1995).…”

Section: Mapping Of Uv Damage In the Mammalian Genome: Effects Of Nucmentioning

confidence: 99%

Mechanisms of UV-induced mutations and skin cancer

Pfeifer

2020

GENOME INSTAB. DIS.

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Ultraviolet (UV) irradiation causes various types of DNA damage, which leads to specific mutations and the emergence of skin cancer in humans, often decades after initial exposure. Different UV wavelengths cause the formation of prominent UV-induced DNA lesions. Most of these lesions are removed by the nucleotide excision repair pathway, which is defective in rare genetic skin disorders referred to as xeroderma pigmentosum. A major role in inducing sunlight-dependent skin cancer mutations is assigned to the cyclobutane pyrimidine dimers (CPDs). In this review, we discuss the mechanisms of UV damage induction, the genomic distribution of this damage, relevant DNA repair mechanisms, the proposed mechanisms of how UV-induced CPDs bring about DNA replication-dependent mutagenicity in mammalian cells, and the strong signature of UV damage and mutagenesis found in skin cancer genomes.Keywords Ultraviolet · UV · Cyclobutane pyrimidine dimer · (6-4) Photoproduct · Mutations · DNA repair · Skin cancer · Melanoma Abbreviations UV light Ultraviolet light CPD Cyclobutane pyrimidine dimer (6-4)PP Pyrimidine (6-4) pyrimidone photoproduct 8-oxo-dG 8-Oxo-7,8-dihydro-2′-deoxyguanosine XP Xeroderma pigmentosum NER Nucleotide excision repair 5mC 5-Methylcytosine

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Section: Mapping Of Uv Damage In the Mammalian Genome: Effects Of Nucmentioning

confidence: 99%

Mechanisms of UV-induced mutations and skin cancer

Pfeifer

2020

GENOME INSTAB. DIS.

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“…1,2 The latter can further evolve into their Dewar isomers through a subsequent photoreaction. 3 While a large amount of theoretical [4][5][6][7][8][9][10][11][12] and experimental [13][14][15][16][17][18][19][20] works have been published on the process leading to cyclobutane pyrimidine dimers, only few researches have been devoted to the elucidation of the mechanism operating in the pyrimidine-pyrimidone (6-4) adducts production. 5,11,[18][19][20][21][22][23][24] The latter reaction is believed to take place through the initial formation of an oxetane or an azedine ring, which constitutes the actual photoproduct, followed by thermal ring opening into the pyrimidine−pyrimidone (6-4) adduct.…”

Section: Introductionmentioning

confidence: 99%

Photoinduced formation mechanism of the thymine–thymine (6–4) adduct in DNA; a QM(CASPT2//CASSCF):MM(AMBER) study

et al. 2018

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The UVB-induced photomechanism leading the carbonyl group of a thymine nucleobase to react with the carbon-carbon double bond of a consecutive thymine nucleobase in a DNA strand to form the thymine-thymine (6-4) photodamage adduct remains poorly understood. Key questions remain unanswered, concerning both the intrinsic features of the photoreaction (such as the contribution (or not) of triplet states, the nature of the involved states and the time-scale of the photoprocess) and the role played by the non-reactive surroundings of the two reactive pyrimidine nucleobases (such as the nature of the flanked nucleobases and the flexibility of the whole DNA molecule). A small number of theoretical studies have been carried out on the title photoreaction, most of which have used reduced model systems of DNA, consequently neglecting potential key parameters for the photoreaction such as the constraints due to the double strain structure and the presence of paired and stacked nucleobases. In the present contribution the photoactivation step of the title reaction has been studied in a DNA system, and in particular for a specific DNA hairpin for which the quantum yield of photodamage formation has been recently experimentally measured. The reaction has been characterized by carrying out high-level QM/MM computations, combining the CASPT2//CASSCF approach for the study of the reactive part (i.e. the two thymine molecules) with an MM-Amber treatment of the surrounding environment. The possibility of a reaction path along both the singlet and triplet manifolds has been characterized, the nature of the reactive states has been analyzed, and the role played by the flexibility of the whole system, which in turn determines the initial accessible geometrical conformations, has been evaluated, thus substantially contributing towards the elucidation of the photoreaction mechanism. On the basis of the obtained results, it can be observed that a charge-transfer state can decay from a pro-reactive initial structure towards a region of energy degeneracy with the ground state, from which the subsequent decay along the ground state hypersurface can lead to the photoreaction.

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“…These methods were initially applied by some of us to perform a decomposition of the absorption spectrum of nucleobase stacks into local, excitonic and charge transfer contributions [ 48 ], to characterize the wavefunctions in an exciplex formed between two adenine molecules [ 69 ] and to monitor excitation energy transfer in dynamics simulations of a DNA model system [ 195 ]. Other groups have subsequently used the formalism to analyze the effects of different stacking interactions [ 17 , 49 ], and the methodology could be generalized for the computation of excitonic coupling elements [ 60 , 196 ]. Related methods were applied in the analysis of double excitations relevant to thymine dimer formation [ 10 ] and to compare the excitations of nucleobases and their thio-substituted analogues [ 9 ].…”

Section: Analysis Of the Resultsmentioning

confidence: 99%

“…The main challenge in this case is the choice of an appropriate functional, where in particular, the fraction of Hartree–Fock exchange has a crucial impact on the resulting excitation energies [ 41 , 44 , 45 ]. The next step on the ladder is given by wavefunction-based methods—for example correlated second-order methods, such as approximate coupled cluster (CC2), algebraic diagrammatic construction (ADC) or perturbatively-corrected configuration interaction with single excitations (e.g., CIS(D))—which can be successfully applied [ 18 , 46 , 47 , 48 , 49 ]. Furthermore, more involved coupled cluster methods have been used to compute the excited states of DNA components [ 50 ].…”

Section: Potential Energy Surfacesmentioning

confidence: 99%

Challenges in Simulating Light-Induced Processes in DNA

et al. 2016

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In this contribution, we give a perspective on the main challenges in performing theoretical simulations of photoinduced phenomena within DNA and its molecular building blocks. We distinguish the different tasks that should be involved in the simulation of a complete DNA strand subject to UV irradiation: (i) stationary quantum chemical computations; (ii) the explicit description of the initial excitation of DNA with light; (iii) modeling the nonadiabatic excited state dynamics; (iv) simulation of the detected experimental observable; and (v) the subsequent analysis of the respective results. We succinctly describe the methods that are currently employed in each of these steps. While for each of them, there are different approaches with different degrees of accuracy, no feasible method exists to tackle all problems at once. Depending on the technique or combination of several ones, it can be problematic to describe the stacking of nucleobases, bond breaking and formation, quantum interferences and tunneling or even simply to characterize the involved wavefunctions. It is therefore argued that more method development and/or the combination of different techniques are urgently required. It is essential also to exercise these new developments in further studies on DNA and subsystems thereof, ideally comprising simulations of all of the different components that occur in the corresponding experiments.

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Noncanonical Stacking Geometries of Nucleobases as a Preferred Target for Solar Radiation

Cited by 14 publications

References 82 publications

Mechanisms of UV-induced mutations and skin cancer

Mechanisms of UV-induced mutations and skin cancer

Photoinduced formation mechanism of the thymine–thymine (6–4) adduct in DNA; a QM(CASPT2//CASSCF):MM(AMBER) study

Challenges in Simulating Light-Induced Processes in DNA

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