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Correlation of bistranded clustered abasic DNA lesion processing with structural and dynamic DNA helix distortion

Abstract : Clustered apurinic/apyrimidinic (AP; abasic) DNA le-sions produced by ionizing radiation are by far more cytotoxic than isolated AP lesion entities. The structure and dynamics of a series of seven 23-bp oligonu-cleotides featuring simple bistranded clustered damage sites, comprising of two AP sites, zero, one, three or five bases 3 or 5 apart from each other, were investigated through 400 ns explicit solvent molecular dynamics simulations. They provide representative structures of synthetically engineered multiply damage sites-containing oligonucleotides whose repair was investigated experimentally (Nucl. Acids Res. 2004, 32:5609-5620; Nucl. Acids Res. 2002, 30: 2800–2808). The inspection of extrahelical positioning of the AP sites, bulge and non Watson–Crick hydrogen bonding corroborates the experimental measurements of repair efficiencies by bacterial or human AP endonucleases Nfo and APE1, respectively. This study provides unprecedented knowledge into the structure and dynamics of clustered abasic DNA lesions, notably rationalizing the non-symmetry with respect to 3 to 5 position. In addition, it provides strong mechanistic insights and basis for future studies on the effects of clustered DNA damage on the recognition and processing of these lesions by bacterial or human DNA repair enzymes specialized in the processing of such lesions.
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Emmanuelle Bignon, Hugo Gattuso, Christophe Morell, François Dehez, Alexandros G. Georgakilas, et al.. Correlation of bistranded clustered abasic DNA lesion processing with structural and dynamic DNA helix distortion. Nucleic Acids Research, Oxford University Press, 2016, 44 (18), pp.8588-8599. ⟨10.1093/nar/gkw773⟩. ⟨hal-01449647⟩

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