Effects of Rett syndrome mutations of the methyl-CpG binding domain of the transcriptional repressor MeCP2 on selectivity for association with methylated DNA
Effects of Rett syndrome mutations of the methyl-CpG binding domain of the transcriptional repressor MeCP2 on selectivity for association with methylated DNA
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DOI：
10.1021/bi0001271
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发表时间：
2000-06-20
期刊：
影响因子：
2.9
通讯作者：
Wolffe, AP
中科院分区：
文献类型：
--
作者：
Ballestar, E;Yusufzai, TM;Wolffe, AP
我们研究了与Rett综合征（一种儿童神经发育障碍）相关的甲基CpG结合转录抑制因子MeCP 2突变形式的特性。我们发现，在甲基CpG结合域（MBD）内的已知位点的四个Rett综合征突变损害与甲基化DNA的结合，但对与非甲基化DNA的非特异性相互作用几乎没有影响。其中三个突变（R106 W、R133 C和F155 S）对甲基化DNA的结合亲和力降低了100倍以上;这与突变MeCP 2对甲基化DNA的选择性受损导致Rett综合征的假设一致。然而，第四个突变体，T158 M，其结合亲和力的甲基化的DNA减少只有2倍，指示与MBD或开发神经元的灵敏度的选择性协会的MeCP 2与甲基化的DNA相关的额外的不同的监管功能。
We have investigated the properties of mutant forms of the methyl-CpG binding transcriptional repressor MeCP2 associated with Rett syndrome, a childhood neurodevelopmental disorder. We find that four Rett syndrome mutations at known sites within the methyl-CpG binding domain (MBD) impair binding to methylated DNA, but have little effect on nonspecific interactions with unmethylated DNA. Three of these mutations (R106W, R133C, and F155S) have their binding affinities for methylated DNA reduced more than 100-fold; this is consistent with the hypothesis that impaired selectivity for methylated DNA of mutant MeCP2 contributes to Rett syndrome. However, a fourth mutant, T158M, has its binding affinity for methylated DNA reduced only 2-fold, indicative either of additional distinct regulatory functions associated with the MBD or of an exquisite sensitivity of developing neurons to the selective association of MeCP2 with methylated DNA.