DNA (6−4) Photolesion Repair Occurs in the Electronic Ground State of the TT Dinucleotide Dimer Radical Anion

Harbach, Philipp H. P.; Borowka, Julia; Bohnwagner, Mercedes-Vanessa; Dreuw, Andreas

doi:10.1021/jz100898x

Cited by 16 publications

(29 citation statements)

References 33 publications

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“…The accuracy of this method has been shown to be about 0.2 eV for typical ππ* and nπ* excitations, which is here sufficient to assign the intermediates in the applied QM/MM framework. In fact, the excitation energies obtained for selected structures in gas phase at SOS‐CIS(D) agree with the ones obtained at higher level of theory such as ADC(2) and CC2 . It must be noted that the electronic spectra reported here refer to vertical excitation to the corresponding lowest excited states (S 1 ).…”

Section: Figuresupporting

confidence: 81%

“…(Figure ). Experimental and theoretical studies have been performed intensively over the past years, to trace all steps of the repair. While the functional mechanism of CPD photolyases has been identified, the details of the repair mechanism operating in (6‐4) photolyases is still a matter of ongoing debate.…”

Section: Figurementioning

confidence: 99%

“…In summary, on the basis of most recent experimental findings along with the geometrical arrangement of the 6‐4PP in the resolved X‐ray structure, the majority of researchers seem to agree that the repair of the 6‐4PP occurs not via formation of a stable oxetane ring prior to the electron transfer. Also, it is now widely accepted that the terminal repair occurs in the electronic ground state of the generated photolesion radical anion. Therefore, we confine ourselves in the following to the steps involved after electron transfer, that is, the electron‐induced repair mechanism, since this catalytic electron triggers the terminal repair.…”

Section: Figurementioning

confidence: 99%

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Characterization of the Intermediate in and Identification of the Repair Mechanism of (6‐4) Photolesions by Photolyases

2016

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Section: Figuresupporting

confidence: 81%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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Characterization of the Intermediate in and Identification of the Repair Mechanism of (6‐4) Photolesions by Photolyases

2016

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Section: Figurementioning

confidence: 99%

Characterization of the Intermediate in and Identification of the Repair Mechanism of (6‐4) Photolesions by Photolyases

2016

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Quantum mechanics/molecular mechanics calculations are employed to assign previously recorded experimental spectroscopic signatures of the intermediates occurring during the photo-induced repair of (6-4) photolesions by photolyases to specific molecular structures. Based on this close comparison of experiment and theory it is demonstrated that the acting repair mechanism involves proton transfer from the protonated His365 to the N3′ nitrogen of the lesion, which proceeds simultaneously with intramolecular OH transfer along an oxetane-like transition state. Keywords(6-4) photoproducts; (6-4) DNA photolyases; DNA repair; photo-induced; proton transfer UV radiation causes two of the most abundant mutagenic and cytotoxic DNA photolesions: cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (6-4PP) [1][2][3][4] . Persistence of these lesions can interfere with essential processes such as transcription and DNA replication leading to mutation, nucleotide misincorporation and eventually to cell death. In fact, (6-4) photoproducts are supposed to be the major players in the formation of skin cancer [5][6][7][8][9] . To maintain genetic integrity, many organisms have developed an elegant mechanism to repair these lesions using photo-activated enzymes called DNA photolyases [10][11][12] . These are highly efficient enzymes utilizing themselves UV/ blue light to eliminate these UV-derived photoproducts. After DNA binding through the dinucleotide flipping mechanism [13] , the enzymatic repair occurs in three sequential steps [5][6][7][8][9][10][11][12][13][14][15][16] : (1) photo-induced electron transfer from the catalytic cofactor, reduced flavine adenine dinucleotide (FADH − ) to the lesion [13][14][15][16][17] (2) electron-induced splitting of the lesion (3) back electron transfer to FADH • (Figure 1). Experimental and theoretical [36][37][38][39][40][41][42][43][44][45][46][47] * shirin.faraji@uni-heidelberg.de.Supporting information for this article is given via a link at the end of the document. HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript studies have been performed intensively over the past years, to trace all steps of the repair. While the functional mechanism of CPD photolyases has been identified [7,8,18,19,23,26,36,37] , the details of the repair mechanism operating in (6-4) photolyases is still a matter of ongoing debate. The initial steps of the repair mechanism, i.e. light absorption, energy transfer [13][14][15] and generation of the catalytic electron [16][17] are now well understood, however, the terminal repair of the 6-4PP after the transfer of the electron is not yet finally determined [40,41,44,47] . Unlike in CPD repair, a single-electron transfer to the 6-4PP is not sufficient [28] for their repair and it was thus suggested that additional factors are required to restore the original bases, which left the field open to hypotheses and speculations. A final proof of the mechanism is hence still missing.The current statu...

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“…For example, in the human body, photoinduced DNA damage is fixed by photolyases -a class of repair enzymes [292,[339][340][341][342][343][344]. The repair mechanism has been the subject of several theoretical studies that arrived at the following scenario: a reduced flavin adenine dinucleotide (FADH À ) transfers one electron (e À ) to the thymine-thymine dimer, the anion formed reverts back to normal thymine bases by ring opening via a radical intermediate, and the electron then returns again to FADH [342,[345][346][347][348][349]. For further information on this topic, we refer the reader to reviews such as [29] and [344].…”

Section: Pyrimidine Dimerizationmentioning

confidence: 99%

Computational Modeling of Photoexcitation in DNA Single and Double Strands

Lü

Lan

Thiel

2014

Topics in Current Chemistry

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The photoexcitation of DNA strands triggers extremely complex photoinduced processes, which cannot be understood solely on the basis of the behavior of the nucleobase building blocks. Decisive factors in DNA oligomers and polymers include collective electronic effects, excitonic coupling, hydrogen-bonding interactions, local steric hindrance, charge transfer, and environmental and solvent effects. This chapter surveys recent theoretical and computational efforts to model real-world excited-state DNA strands using a variety of established and emerging theoretical methods. One central issue is the role of localized vs delocalized excitations and the extent to which they determine the nature and the temporal evolution of the initial photoexcitation in DNA strands.

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DNA (6−4) Photolesion Repair Occurs in the Electronic Ground State of the TT Dinucleotide Dimer Radical Anion

Cited by 16 publications

References 33 publications

Characterization of the Intermediate in and Identification of the Repair Mechanism of (6‐4) Photolesions by Photolyases

Characterization of the Intermediate in and Identification of the Repair Mechanism of (6‐4) Photolesions by Photolyases

Characterization of the Intermediate in and Identification of the Repair Mechanism of (6‐4) Photolesions by Photolyases

Computational Modeling of Photoexcitation in DNA Single and Double Strands

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