Mutations in DNA methyltransferase DNMT3B in ICF syndrome affect its regulation by DNMT3L.
Mutations in DNA methyltransferase DNMT3B in ICF syndrome affect its regulation by DNMT3L.
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DOI：
10.1093/hmg/ddl059
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发表时间：
2006-05
影响因子：
3.5
通讯作者：
Zheng-Hua Xie;Yan-Nv Huang;Zhao-xia Chen;A. Riggs;Jian-ping Ding;H. Gowher;A. Jeltsch;H. Sasaki;K. Hata;Guo-Liang Xu
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文献类型：
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作者：
Zheng-Hua Xie;Yan-Nv Huang;Zhao-xia Chen;A. Riggs;Jian-ping Ding;H. Gowher;A. Jeltsch;H. Sasaki;K. Hata;Guo-Liang Xu
DNA 甲基转移酶 DNMT3B 缺陷会导致一种隐性人类疾病，其特征是免疫缺陷、着丝粒不稳定和与基因组甲基化缺陷相关的面部异常 (ICF)。大多数 ICF 突变是 DNMT3B 保守催化结构域中的单个氨基酸取代，这被认为直接损害其酶活性。发育过程中完整基因组甲基化模式的建立需要通过包括具有刺激作用的DNMT3L在内的调节因子对两种相关甲基转移酶DNMT3A和DNMT3B的从头甲基化活性进行精细调节。在这里，我们发现两个具有 ICF 引起取代的 DNMT3B 突变蛋白（A766P 和 R840Q）在体外和体内表现出与野生型酶相似的甲基化活性。然而，由于蛋白质相互作用不足，DNMT3L 对它们的刺激受到严重影响。我们的研究结果表明，ICF 综合征中的甲基化缺陷也可能是由于 DNMT3L 或其他未知调节因素对 DNMT3B 活性的刺激受损以及突变 DNMT3B 蛋白本身的基础催化活性减弱所致。
Deficiency in DNA methyltransferase DNMT3B causes a recessive human disorder characterized by immunodeficiency, centromeric instability and facial anomalies (ICF) in association with defects in genomic methylation. The majority of ICF mutations are single amino acid substitutions in the conserved catalytic domain of DNMT3B, which are believed to impair its enzymatic activity directly. The establishment of intact genomic methylation patterns in development requires a fine regulation of the de novo methylation activity of the two related methyltransferases DNMT3A and DNMT3B by regulatory factors including DNMT3L which has a stimulatory effect. Here, we show that two DNMT3B mutant proteins with ICF-causing substitution (A766P and R840Q) displayed a methylation activity similar to the wild-type enzyme both in vitro and in vivo. However, their stimulation by DNMT3L was severely compromised due to deficient protein interaction. Our findings suggest that methylation defects in ICF syndrome may also result from impaired stimulation of DNMT3B activity by DNMT3L or other unknown regulatory factors as well as from a weakened basal catalytic activity of the mutant DNMT3B protein per se.