Repair Rate of Clustered Abasic DNA Lesions by Human Endonuclease: Molecular Bases of Sequence Specificity.
In the present contribution, the interaction between damaged DNA and repair enzymes is examined by means of molecular dynamics simulations. More specifically, we consider clustered abasic DNA lesions processed by the primary human apurinic/apyrimidinic (AP) endonuclease, APE1. Our results show that, in stark contrast with the corresponding bacterial endonucleases, human APE1 imposes strong geometrical constraints on the DNA duplex. As a consequence, the level of recognition and, hence, the repair rate is higher. Important features that guide the DNA/protein interactions are the presence of an extended positively charged region and of a molecular tweezers that strongly constrains DNA. Our results are on very good agreement with the experimentally determined repair rate of clustered abasic lesions. The lack of repair for one particular arrangement of the two abasic sites is also explained considering the peculiar destabilizing interaction between the recognition region and the second lesion, resulting in a partial opening of the molecular tweezers and, thus, a less stable complex. This contribution cogently establishes the molecular bases for the recognition and repair of clustered DNA lesions by means of human endonucleases.
Université de Lorraine-Nancy , Theory-Modeling-Simulation SRSMC, 54000 Vandoeuvre-lès-Nancy, France.|CNRS , Theory-Modeling-Simulation SRSMC, 54000 Vandoeuvre-lès-Nancy, France.
Hugo
H
Gattuso
Université de Lorraine-Nancy , Theory-Modeling-Simulation SRSMC, 54000 Vandoeuvre-lès-Nancy, France.|CNRS , Theory-Modeling-Simulation SRSMC, 54000 Vandoeuvre-lès-Nancy, France.
Elodie
E
Durand
Univ Lyon, Ens de Lyon, CNRS UMR 5182, Université Claude Bernard Lyon 1 , Laboratoire de Chimie, F-69342 Lyon, France.|Université de Lyon , Institut des Sciences Analytiques UMR 5280, CNRS, Université de Lyon 1, ENS Lyon 5 rue de la Doua, F-69100 Villeurbanne, France.
Emmanuelle
E
Bignon
Université de Lyon , Institut des Sciences Analytiques UMR 5280, CNRS, Université de Lyon 1, ENS Lyon 5 rue de la Doua, F-69100 Villeurbanne, France.
Christophe
C
Morell
DNA damage laboratory, Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens (NTUA) , Zografou, Athens 15780, Greece.
Alexandros G
AG
Georgakilas
Univ Lyon, Ens de Lyon, CNRS UMR 5182, Université Claude Bernard Lyon 1 , Laboratoire de Chimie, F-69342 Lyon, France.
Elise
E
Dumont
Université de Lorraine-Nancy , Theory-Modeling-Simulation SRSMC, 54000 Vandoeuvre-lès-Nancy, France.|CNRS , Theory-Modeling-Simulation SRSMC, 54000 Vandoeuvre-lès-Nancy, France.|Department of Physics, University of Illinois at Urbana-Champaign , 1110 West Green Street, Urbana, Illinois 61801, United States.|Laboratoire International Associé Centre National de la Recherche Scientifique et University of Illinois at Urbana-Champaign.
Christophe
C
Chipot
Université de Lorraine-Nancy , Theory-Modeling-Simulation SRSMC, 54000 Vandoeuvre-lès-Nancy, France.|CNRS , Theory-Modeling-Simulation SRSMC, 54000 Vandoeuvre-lès-Nancy, France.|Laboratoire International Associé Centre National de la Recherche Scientifique et University of Illinois at Urbana-Champaign.
François
F
Dehez
Université de Lorraine-Nancy , Theory-Modeling-Simulation SRSMC, 54000 Vandoeuvre-lès-Nancy, France.|CNRS , Theory-Modeling-Simulation SRSMC, 54000 Vandoeuvre-lès-Nancy, France.
Antonio
A
Monari
D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation; D009690:Nucleic Acid Conformation; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity
D001426:Bacterial Proteins; D004247:DNA; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase