Synergistic modulation of cyclobutane pyrimidine dimer photoproduct formation and deamination at a TmCG site over a full helical DNA turn in a nucleosome core particle.
Sunlight-induced C to T mutation hotspots in skin cancers occur primarily at methylated CpG sites that coincide with sites of UV-induced cyclobutane pyrimidine dimer (CPD) formation. The C or 5-methyl-C in CPDs are not stable and deaminate to U and T, respectively, which leads to the insertion of A by DNA polymerase η and defines a probable mechanism for the origin of UV-induced C to T mutations. We have now determined the photoproduct formation and deamination rates for 10 consecutive T=(m)CG CPDs over a full helical turn at the dyad axis of a nucleosome and find that whereas photoproduct formation and deamination is greatly inhibited for the CPDs closest to the histone surface, it is greatly enhanced for the outermost CPDs. Replacing the G in a T=(m)CG CPD with A greatly decreased the deamination rate. These results show that rotational position and flanking sequence in a nucleosome can significantly and synergistically modulate CPD formation and deamination that contribute to C to T mutations associated with skin cancer induction and may have influenced the evolution of the human genome.
Department of Chemistry, Washington University, St. Louis, MO 63130, USA.
Qian
Q
Song
Department of Chemistry, Washington University, St. Louis, MO 63130, USA.
Vincent J
VJ
Cannistraro
Department of Chemistry, Washington University, St. Louis, MO 63130, USA taylor@wustl.edu.
John-Stephen
JS
Taylor
D004247:DNA / Q000737:chemistry*; D003641:Deamination; D009154:Mutation; D059645:Mutation Rate; D009707:Nucleosomes / Q000737:chemistry*; D011740:Pyrimidine Dimers / Q000737:chemistry*
D009707:Nucleosomes; D011740:Pyrimidine Dimers; D004247:DNA