CDCA7 is a hemimethylated DNA adaptor for the nucleosome remodeler HELLS.
CDCA7 is a hemimethylated DNA adaptor for the nucleosome remodeler HELLS.
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CDCA7 是核小体重塑剂 HELLS 的半甲基化 DNA 接头。
DOI：
10.1101/2023.12.19.572350
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Funabiki,Hironori
中科院分区：
文献类型：
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作者：
Wassing,IsabelE;Nishiyama,Atsuya;Hiruta,Moeri;Jia,Qingyuan;Shikimachi,Reia;Kikuchi,Amika;Sugimura,Keita;Hong,Xin;Chiba,Yoshie;Peng,Junhui;Jenness,Christopher;Nakanishi,Makoto;Zhao,Li;Arita,Kyohei;Funabiki,Hironori
SNF2家族ATPase Hells及其激活子CDCA7的突变导致免疫缺陷-着丝粒不稳定-面部畸形(ICF)综合征，其特征是异染色质低甲基化。CDCA7独特的锌指结构域ZF-4CXXC_R1在真核生物中广泛保守，但在缺乏Hells和DNA甲基转移酶的物种中不存在，这意味着它与DNA甲基化有特殊的关系。在这里，我们证明了ZF-4CXXC_R1作为半甲基化的DNA传感器。CDCA7的ZF-4CXXC_R1结构域通过半甲基化的CpG选择性地与DNA结合，而不是未甲基化或完全甲基化的CpG，ICF疾病突变消除了这种结合。CDCA7和Hells通过其N端的α螺旋相互作用，Hells通过该螺旋被招募到半甲基化的DNA中。虽然半甲基化的CpG位于核小体核心颗粒中会阻碍CDCA7对其的识别，但对CDCA7-核小体复合体的冷冻EM结构分析表明，ZF-4CXXC_R1在连接子DNA的主槽中识别半甲基化的CpG。我们的研究为CDCA7-Hells核小体重塑复合体如何独特地协助维持DNA甲基化提供了见解。
Mutations of the SNF2 family ATPase HELLS and its activator CDCA7 cause immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome, characterized by hypomethylation at heterochromatin. The unique zinc-finger domain, zf-4CXXC_R1, of CDCA7 is widely conserved across eukaryotes but is absent from species that lack HELLS and DNA methyltransferases, implying its specialized relation with methylated DNA. Here we demonstrate that zf-4CXXC_R1 acts as a hemimethylated DNA sensor. The zf-4CXXC_R1 domain of CDCA7 selectively binds to DNA with a hemimethylated CpG, but not unmethylated or fully methylated CpG, and ICF disease mutations eliminated this binding. CDCA7 and HELLS interact via their N-terminal alpha helices, through which HELLS is recruited to hemimethylated DNA. While placement of a hemimethylated CpG within the nucleosome core particle can hinder its recognition by CDCA7, cryo-EM structure analysis of the CDCA7-nucleosome complex suggests that zf-4CXXC_R1 recognizes a hemimethylated CpG in the major groove at linker DNA. Our study provides insights into how the CDCA7-HELLS nucleosome remodeling complex uniquely assists maintenance DNA methylation.