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Solution structure of duplex DNA containing a ?-carba-Fapy-dG lesion.

ABSTRACT: The addition of hydroxyl radicals to the C8 position of guanine can lead to the formation of a 2,6-diamino-4-hydroxy-5-formamido-2'-deoxypyrimidine (Fapy-dG) lesion, whose endogenous levels in cellular DNA rival those of 8-oxo-7,8-dihydroxy-2'-deoxyguanosine. Despite its prevalence, the structure of duplex DNA containing Fapy-dG is unknown. We have prepared an undecameric duplex containing a centrally located ?-cFapy-dG residue paired to dC and determined its solution structure by high-resolution NMR spectroscopy and restrained molecular dynamic simulations. The damaged duplex adopts a right-handed helical structure with all residues in an anti conformation, forming Watson-Crick base pair alignments, and 2-deoxyribose conformations in the C2'-endo/C1'-exo range. The formamido group of Fapy rotates out of the pyrimidine plane and is present in the Z and E configurations that equilibrate with an approximate 2:1 population ratio. The two isomeric duplexes show similar lesion-induced deviations from a canonical B-from DNA conformation that are minor and limited to the central three-base-pair segment of the duplex, affecting the stacking interactions with the 5-lesion-neighboring residue. We discuss the implications of our observations for translesion synthesis during DNA replication and the recognition of Fapy-dG by DNA glycosylases.

SUBMITTER: Lukin M

PROVIDER: S-EPMC3502696 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Solution structure of duplex DNA containing a β-carba-Fapy-dG lesion.

Lukin Mark M Zaliznyak Tatiana T Attaluri Sivaprasad S Johnson Francis F de Los Santos Carlos C

Chemical research in toxicology 20120829 11

The addition of hydroxyl radicals to the C8 position of guanine can lead to the formation of a 2,6-diamino-4-hydroxy-5-formamido-2'-deoxypyrimidine (Fapy-dG) lesion, whose endogenous levels in cellular DNA rival those of 8-oxo-7,8-dihydroxy-2'-deoxyguanosine. Despite its prevalence, the structure of duplex DNA containing Fapy-dG is unknown. We have prepared an undecameric duplex containing a centrally located β-cFapy-dG residue paired to dC and determined its solution structure by high-resolutio ...[more]

PMID: 22897814

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Project description:Genetic information, irrespective of cell type (normal or cancerous), is exposed to a range of harmful factors, which can lead to more than 80 different types of DNA damage. Of these, oxoG and FapyG have been identified as the most abundant in normoxic and hypoxic conditions, respectively. This article considers d[AFapyGAOXOGA]*[TCTCT] (oligo-FapyG) with clustered DNA lesions (CDLs) containing both the above types of damage at the M06-2x/6-31++G** level of theory in the condensed phase. Furthermore, the electronic properties of oligo-FapyG were analysed in both equilibrated and non-equilibrated solvation-solute interaction modes. The vertical/adiabatic ionization potential (VIP, AIP) and electron affinity (VEA, AEA) of the investigated ds-oligo were found as follows in [eV]: 5.87/5.39 and -1.41/-2.09, respectively. The optimization of the four ds-DNA spatial geometries revealed that the transFapydG was energetically privileged. Additionally, CDLs were found to have little influence on the ds-oligo structure. Furthermore, for the FapyGC base-pair isolated from the discussed ds-oligo, the ionization potential and electron affinity values were higher than those assigned to OXOGC. Finally, a comparison of the influence of FapyGC and OXOGC on charge transfer revealed that, in contrast to the OXOGC base-pair, which, as expected, acted as a radical cation/anion sink in the oligo-FapyG structure, FapyGC did not significantly affect charge transfer (electron-hole and excess-electron). The results presented below indicate that 7,8-dihydro-8-oxo-2'-deoxyguanosine plays a significant role in charge transfer through ds-DNA containing CDL and indirectly has an influence on the DNA lesion recognition and repair process. In contrast, the electronic properties obtained for 2,6-diamino-4-hydroxy-5-foramido-2'deoxypyrimidine were found to be too weak to compete with OXOG to influence charge transfer through the discussed ds-DNA containing CDL. Because increases in multi-damage site formation are observed during radio- or chemotherapy, understanding their role in the above processes can be crucial for the efficiency and safety of medical cancer treatment.

Dataset Information

Solution structure of duplex DNA containing a ?-carba-Fapy-dG lesion.

Publications

Solution structure of duplex DNA containing a β-carba-Fapy-dG lesion.

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