The Conformation of the Complementary Strand and the Deformation of the DNA Groove upon DDB2 Binding Justifies the Different Repair Rates for Cyclobutane Pyrimidine Dimers.

Abstract

The repair of photo-induced DNA lesions through nucleotide excision repair machinery is still the source of important questions. It has been observed that the repair rate of the different cyclobutane pyrimidine dimers, i.e. the photoproducts induced by dimerization of two {pi}-stacked pyrimidines (T<>T, T<>C, C<>T, C<>C), depends on the nucleobases involved in the lesion. TT derivatives (T<>T) are removed more slowly than those containing cytosine, especially in 5. Using all-atom molecular dynamics simulations, we demonstrate that the variation of the repair rate observed in human skin and in cultured cutaneous cell may be associated to the recognition of the four lesions by the DDB2 protein moiety, and more specifically by the differential structural deformation induced on the complementary strand and the major groove. These effects may then hamper differentially the downstream recruitment of the repair complexes. The observed DNA deformation correlates with the experimental repair rate and suggests a structural rationale for the different repair rates of CPD by nucleotide excision repair machinery. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=186 SRC="FIGDIR/small/724087v2_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@1c02e6forg.highwire.dtl.DTLVardef@28b3c1org.highwire.dtl.DTLVardef@3143fborg.highwire.dtl.DTLVardef@664d48_HPS_FORMAT_FIGEXP M_FIG C_FIG