Methyl CpG binding protein 2 (MeCP2) enhances photodimer formation at methyl-CpG sites but suppresses dimer deamination.
Spontaneous deamination of cytosine to uracil in DNA is a ubiquitous source of C→T mutations, but occurs with a half life of ∼50 000 years. In contrast, cytosine within sunlight induced cyclobutane dipyrimidine dimers (CPD's), deaminate within hours to days. Methylation of C increases the frequency of CPD formation at PyCG sites which correlate with C→T mutation hotspots in skin cancers. MeCP2 binds to mCG sites and acts as a transcriptional regulator and chromatin modifier affecting thousands of genes, but its effect on CPD formation and deamination is unknown. We report that the methyl CpG binding domain of MeCP2 (MBD) greatly enhances C=mC CPD formation at a TCmCG site in duplex DNA and binds with equal or better affinity to the CPD-containing duplex compared with the undamaged duplex. In comparison, MBD does not enhance T=mC CPD formation at a TTmCG site, but instead increases CPD formation at the adjacent TT site. MBD was also found to completely suppress deamination of the T=mCG CPD, suggesting that MeCP2 may have the capability to both suppress UV mutagenesis at PymCpG sites as well as enhance it.
Cannistraro
Vincent J
VJ
Department of Chemistry, Washington University, St Louis, MO 63130, USA.
Taylor
John-Stephen A
JS
D018899:CpG Islands / Q000528:radiation effects; D018983:DNA Footprinting; D019175:DNA Methylation; D003641:Deamination; D019281:Dimerization; D051783:Methyl-CpG-Binding Protein 2 / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011740:Pyrimidine Dimers / Q000737:chemistry*; D014443:Tyrosine / Q000737:chemistry; D014466:Ultraviolet Rays
D051783:Methyl-CpG-Binding Protein 2; D011740:Pyrimidine Dimers; D014443:Tyrosine