title: Correlation of bistranded clustered abasic DNA lesion processing with structural and dynamic DNA helix distortion.
abstract: Clustered apurinic/apyrimidinic (AP; abasic) DNA lesions 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 oligonucleotides 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.
authors: Univ Lyon, Ens de Lyon, CNRS, Université Lyon 1, Laboratoire de Chimie UMR 5182, F-69342, Lyon, France Institut des Sciences Analytiques, Université de Lyon 1 and CNRS, F-69100, Villeurbanne France.
authors: Emmanuelle
authors: E
authors: Bignon
authors: Université de Lorraine -Nancy, Theory-Modeling-Simulation SRSMC, F-54506, Vandoeuvre-lès-Nancy, France CNRS, Theory-Modeling-Simulation SRSMC, F-54506, Vandoeuvre-lès-Nancy, France.
authors: Hugo
authors: H
authors: Gattuso
authors: Institut des Sciences Analytiques, Université de Lyon 1 and CNRS, F-69100, Villeurbanne France.
authors: Christophe
authors: C
authors: Morell
authors: Université de Lorraine -Nancy, Theory-Modeling-Simulation SRSMC, F-54506, Vandoeuvre-lès-Nancy, France CNRS, Theory-Modeling-Simulation SRSMC, F-54506, Vandoeuvre-lès-Nancy, France.
authors: François
authors: F
authors: Dehez
authors: DNA damage laboratory, Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens (NTUA), Zografou 15780, Athens, Greece alexg@mail.ntua.gr.
authors: Alexandros G
authors: AG
authors: Georgakilas
authors: Université de Lorraine -Nancy, Theory-Modeling-Simulation SRSMC, F-54506, Vandoeuvre-lès-Nancy, France CNRS, Theory-Modeling-Simulation SRSMC, F-54506, Vandoeuvre-lès-Nancy, France antonio.monari@univ-lorraine.fr.
authors: Antonio
authors: A
authors: Monari
authors: Univ Lyon, Ens de Lyon, CNRS, Université Lyon 1, Laboratoire de Chimie UMR 5182, F-69342, Lyon, France elise.dumont@ens-lyon.fr.
authors: Elise
authors: E
authors: Dumont
mesh_terms: D001483:Base Sequence; D004247:DNA / Q000737:chemistry*; D004249:DNA Damage; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D009690:Nucleic Acid Conformation; D013997:Time Factors
chemical_list: D004247:DNA; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase