Laboratory of Chromosome and Cell Biology, The Rockefeller University, New York, NY 10065, USA.
Division of Cancer Cell Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Tokyo 108-8639, Japan.
Sci Adv. 2024 Aug 23;10(34):eadp5753. doi: 10.1126/sciadv.adp5753.
Mutations of the SNF2 family ATPase HELLS and its activator CDCA7 cause immunodeficiency, centromeric instability, and facial anomalies syndrome, characterized by DNA hypomethylation at heterochromatin. It remains unclear why CDCA7-HELLS is the sole nucleosome remodeling complex whose deficiency abrogates the maintenance of DNA methylation. We here identify the unique zinc-finger domain of CDCA7 as an evolutionarily conserved hemimethylation-sensing zinc finger (HMZF) domain. Cryo-electron microscopy structural analysis of the CDCA7-nucleosome complex reveals that the HMZF domain can recognize hemimethylated CpG in the outward-facing DNA major groove within the nucleosome core particle, whereas UHRF1, the critical activator of the maintenance methyltransferase DNMT1, cannot. CDCA7 recruits HELLS to hemimethylated chromatin and facilitates UHRF1-mediated H3 ubiquitylation associated with replication-uncoupled maintenance DNA methylation. We propose that the CDCA7-HELLS nucleosome remodeling complex assists the maintenance of DNA methylation on chromatin by sensing hemimethylated CpG that is otherwise inaccessible to UHRF1 and DNMT1.
SNF2 家族 ATP 酶 HELLS 和其激活因子 CDCA7 的突变会导致免疫缺陷、着丝粒不稳定和面部异常综合征，其特征是异染色质的 DNA 低甲基化。目前尚不清楚为什么 CDCA7-HELLS 是唯一的核小体重塑复合物，其缺乏会破坏 DNA 甲基化的维持。在这里，我们确定了 CDCA7 的独特锌指结构域是一个进化上保守的半甲基化感应锌指（HMZF）结构域。CDCA7-核小体复合物的冷冻电子显微镜结构分析表明，HMZF 结构域可以识别核小体核心颗粒中向外开放的 DNA 大沟中的半甲基化 CpG，而维持甲基转移酶 DNMT1 的关键激活因子 UHRF1 则不能。CDCA7 将 HELLS 募集到半甲基化染色质上，并促进 UHRF1 介导的与复制解耦的维持 DNA 甲基化相关的 H3 泛素化。我们提出，CDCA7-HELLS 核小体重塑复合物通过感应否则无法被 UHRF1 和 DNMT1 接近的半甲基化 CpG，协助染色质上的 DNA 甲基化维持。
