Rotational Position of a 5-Methylcytosine-containing Cyclobutane Pyrimidine Dimer in a Nucleosome Greatly Affects Its Deamination Rate

• Published in: The Journal of biological chemistry 2011-02, Vol.286 (8), p.6329-6335
• Main Authors: Song, Qian, Cannistraro, Vincent J., Taylor, John-Stephen
• Format: Article
• Language: English
• Subjects: 5-Methylcytosine - chemistry; 5-Methylcytosine - metabolism; Animals; Deamination; Deamination - radiation effects; DNA - chemistry; DNA - metabolism; DNA and Chromosomes; DNA Damage; DNA Methylation; Histones; Methylcytosine; Models, Molecular; Mutagenesis - radiation effects; Mutagenesis Mechanisms; Nucleic Acid Chemistry; Nucleic Acid Structure; Nucleosome; Nucleosomes - chemistry; Nucleosomes - metabolism; Photoproduct; Pyrimidine Dimers - chemistry; Pyrimidine Dimers - metabolism; Ultraviolet Rays; Xenopus laevis
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.183178

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. These mutations are proposed to arise from the insertion of A by DNA polymerase η opposite the T that results from deamination of the methylC (mC) within the CPD. Although the frequency of CPD formation and repair is modestly modulated by its rotational position within a nucleosome, the effect of position on the rate of mC deamination in a CPD has not been previously studied. We now report that deamination of a TmC CPD whose sugar phosphate backbone is positioned against the histone core surface decreases by a factor of 4.7, whereas that of a TmC CPD positioned away from the surface increases by a factor of 8.9 when compared with unbound DNA. Because the mCs undergoing deamination are in similar steric environments, the difference in rate appears to be a consequence of a difference in the flexibility and compression of the two sites due to DNA bending. Considering that formation of the CPD positioned away from the surface is also enhanced by a factor of two, a TmCG site in this position might be expected to have up to an 84-fold higher probability of resulting in a UV-induced mC to T mutation than one positioned against the surface. These results indicate that rotational position may play an important role in the formation of UV-induced C to T mutation hotspots, as well as in the mutagenic mechanism of other DNA lesions.