Conformational polymorphism or structural invariance in DNA photoinduced lesions: implications for repair rates.
DNA photolesions constitute a particularly deleterious class of molecular defects responsible for the insurgence of a vast majority of skin malignant tumors. Dimerization of two adjacent thymines or cytosines mostly gives rise to cyclobutane pyrimidine dimers (CPD) and pyrimidine(6-4)pyrimidone 64-PP as the most common defects. We perform all-atom classical simulations, up to 2 μs, of CPD and 64-PP embedded in a 16-bp duplex, which reveal the constrasted behavior of the two lesions. In particular we evidence a very limited structural deformation induced by CPD while 64-PP is characterized by a complex structural polymorphism. Our simulations also allow to unify the contrasting experimental structural results obtained by nuclear magnetic resonance or Förster Resonant Energy Transfer method, showing that both low and high bent structures are indeed accessible. These contrasting behaviors can also explain repair resistance or the different replication obstruction, and hence the genotoxicity of these two photolesions.
CNRS, Theory-Modeling-Simulation, SRSMC F-54506 Vandoeuvre-lès-Nancy, France.|Université de Lorraine, Theory-Modeling-Simulation, SRSMC F-54506 Vandoeuvre-lès-Nancy, France.|Laboratoire International Associé Centre National de la Recherche Scientifique et University of Illinois at Urbana Champaign.
François
F
Dehez
CNRS, Theory-Modeling-Simulation, SRSMC F-54506 Vandoeuvre-lès-Nancy, France.|Université de Lorraine, Theory-Modeling-Simulation, SRSMC F-54506 Vandoeuvre-lès-Nancy, France.
Hugo
H
Gattuso
Institut des Sciences Analytiques, UMR 5280, Université de Lyon1 (UCBL) CNRS, ENS Lyon, Lyon, France.|Université de Lyon, ENS de Lyon, CNRS, Université Lyon 1, Laboratoire de Chimie UMR 5182, F69342 Lyon, France.
Emmanuelle
E
Bignon
Institut des Sciences Analytiques, UMR 5280, Université de Lyon1 (UCBL) CNRS, ENS Lyon, Lyon, France.
Christophe
C
Morell
Université de Lyon, ENS de Lyon, CNRS, Université Lyon 1, Laboratoire de Chimie UMR 5182, F69342 Lyon, France.
Elise
E
Dumont
CNRS, Theory-Modeling-Simulation, SRSMC F-54506 Vandoeuvre-lès-Nancy, France.|Université de Lorraine, Theory-Modeling-Simulation, SRSMC F-54506 Vandoeuvre-lès-Nancy, France.
Antonio
A
Monari
D004260:DNA Repair; D059371:DNA, B-Form / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D009690:Nucleic Acid Conformation; D011740:Pyrimidine Dimers / Q000737:chemistry*
D059371:DNA, B-Form; D011740:Pyrimidine Dimers; C058406:pyrimidine-pyrimidone dimer