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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Methylated DNA-binding domain 1 and methylpurine-DNA glycosylase link transcriptional repression and DNA repair in chromatin
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Methylated DNA-binding domain 1 and methylpurine-DNA glycosylase link transcriptional repression and DNA repair in chromatin

机译：甲基化DNA结合域1和甲基嘌呤-DNA糖基化酶连接染色质的转录抑制和DNA修复

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摘要

The methyl-CpG dinucleotide containing a symmetrical 5-methylcy-tosine (mC) is involved in gene regulation and genome stability. We report here that methylation-mediated transcriptional repressor methylated DNA-binding domain 1 (MBD1) interacts with methylpurine-DNA glycosylase (MPG), which excises damaged bases from substrate DNA. MPG itself actively represses transcription and has a synergistic effect on gene silencing together with MBD1. Chromatin immunoprecipitation analysis reveals the molecular movement of MBD1 and MPG in vivo: (ⅰ) The MBD1-MPG complex normally exists on the methylated gene promoter; (ⅱ) treatment of cells with alky-lating agent methylmethanesulfonate (MMS) induces the dissociation of MBD1 from the methylated promoter, and MPG is located on both methylated and unmethylated promoters; and (ⅲ) after completion of the repair, the MBD1-MPG complex is restored on the methylated promoter. Mobility-shift and structural analyses show that the MBD of MBD1 binds a methyl-CpG pair (mCpG x mCpG) but not the methyl-CpG pair containing a single 7-methylguanine (N) (mCpG x mCpN) that is known as one of the major lesions caused by MMS. We further demonstrate that knockdown of MBD1 by specific small interfering RNAs significantly increases cell sensitivity to MMS. These data suggest that MBD1 cooperates with MPG for transcriptional repression and DNA repair. We hypothesize that MBD1 functions as a reservoir for MPG and senses the base damage in chromatin.
机译：包含对称的5-甲基半胱氨酸（mC）的甲基CpG二核苷酸参与基因调控和基因组稳定性。我们在这里报告，甲基化介导的转录阻遏物甲基化的DNA结合域1（MBD1）与甲基嘌呤-DNA糖基化酶（MPG）相互作用，后者可从底物DNA中切除受损的碱基。 MPG本身可积极抑制转录，并与MBD1一起对基因沉默产生协同作用。染色质免疫沉淀分析揭示了MBD1和MPG在体内的分子运动：（ⅰ）MBD1-MPG复合物通常存在于甲基化基因启动子上； （ⅱ）用烷基化剂甲磺酸甲酯（MMS）处理细胞会诱导MBD1从甲基化启动子上解离，而MPG既位于甲基化启动子上，又位于未甲基化启动子上； （ⅲ）修复完成后，MBD1-MPG复合物在甲基化的启动子上恢复。移动性和结构分析表明，MBD1的MBD与甲基CpG对（mCpG x mCpG）结合，但不与包含单个7-甲基鸟嘌呤（N）（mCpG x mCpN）的甲基CpG对结合。 MMS引起的主要病变。我们进一步证明，通过特定的小分子干扰RNA敲低MBD1会显着增加细胞对MMS的敏感性。这些数据表明MBD1与MPG合作进行转录抑制和DNA修复。我们假设MBD1充当MPG的储存器，并检测染色质的碱基损伤。

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