Comprehensive structure-function characterization of DNMT3B and DNMT3A reveals distinctive de novo DNA methylation mechanisms
Comprehensive structure-function characterization of DNMT3B and DNMT3A reveals distinctive de novo DNA methylation mechanisms
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DOI：
10.1038/s41467-020-17109-4
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发表时间：
2020-07-03
影响因子：
16.6
通讯作者：
Song, Jikui
中科院分区：
文献类型：
--
作者：
Gao, Linfeng;Emperle, Max;Song, Jikui
哺乳动物DNA甲基化模式是由两个新的DNA甲基转移酶DNMT3A和DNMT3B建立的，它们表现出冗余和独特的甲基化活性。然而，相关的分子基础仍未确定。通过对DNMT3A和DNMT3B的全面结构、酶学和细胞特征分析，我们在此报告了一种多层底物识别机制，支持它们不同的基因组甲基化活性。DNMT3B催化环中的氢键导致CpG特异性低于DNMT3A，而目标识别结构域和同型二聚体界面的相互作用微调了两种酶之间不同的目标选择，DNMT3B的赖氨酸777作为+1侧翼碱基的独特传感器。DNMT3A和DNMT3B之间不同的底物偏好为DNMT3B突变的ICF综合征中出现的位点特异性表观基因组改变提供了解释。总之，这项研究揭示了两种DNMT3酶的不同底物读出机制，暗示了它们在发育和发病机制中的不同作用。在哺乳动物中，DNA甲基化模式是由两种新的DNA甲基转移酶DNMT3A和DNMT3B建立的。在这里，作者报告了DNMT3B与CpG和CpA DNA复合物的晶体结构，为DNMT3A和DNMT3B不同基因组甲基化活性的底物识别机制提供了深入的见解。
Mammalian DNA methylation patterns are established by two de novo DNA methyltransferases, DNMT3A and DNMT3B, which exhibit both redundant and distinctive methylation activities. However, the related molecular basis remains undetermined. Through comprehensive structural, enzymology and cellular characterization of DNMT3A and DNMT3B, we here report a multi-layered substrate-recognition mechanism underpinning their divergent genomic methylation activities. A hydrogen bond in the catalytic loop of DNMT3B causes a lower CpG specificity than DNMT3A, while the interplay of target recognition domain and homodimeric interface fine-tunes the distinct target selection between the two enzymes, with Lysine 777 of DNMT3B acting as a unique sensor of the +1 flanking base. The divergent substrate preference between DNMT3A and DNMT3B provides an explanation for site-specific epigenomic alterations seen in ICF syndrome with DNMT3B mutations. Together, this study reveals distinctive substrate-readout mechanisms of the two DNMT3 enzymes, implicative of their differential roles during development and pathogenesis. In mammals, DNA methylation patterns are established by two de novo DNA methyltransferases, DNMT3A and DNMT3B. Here the authors report the crystal structures of DNMT3B in complex with both CpG and CpA DNA, providing insight into the substrate-recognition mechanism underpinning the divergent genomic methylation activities of DNMT3A and DNMT3B.