CDCA7 is an evolutionarily conserved hemimethylated DNA sensor in eukaryotes

• DOI: 10.1126/sciadv.adp5753
• Publication Date: 2024-08-23T17:58:55Z
• Authors: Isabel E. Wassing; Atsuya Nishiyama; Reia Shikimachi; Qingyuan Jia; Amika Kikuchi; Moeri Hiruta; Keita Sugimura; Xin Hong; Yoshie Chiba; Junhui Peng; Christopher Jenness; Makoto Nakanishi; Li Zhao; Kyohei Arita; Hironori Funabiki
• Keywords: DNA (Cytosine-5-)-Methyltransferase 1; Adenosine Triphosphatases; 0301 basic medicine; Ubiquitin-Protein Ligases; Cryoelectron Microscopy; Ubiquitination; DNA Helicases; Nuclear Proteins; Eukaryota; Cell Cycle Proteins; Zinc Fingers; DNA; DNA Methylation; Chromatin; Nucleosomes; Evolution, Molecular; Histones; 03 medical and health sciences; CCAAT-Enhancer-Binding Proteins; Humans; CpG Islands; Biomedicine and Life Sciences; Protein Binding

Mutations of the SNF2 family ATPase HELLS and its activator CDCA7 cause immunodeficiency, centromeric instability, facial anomalies syndrome, characterized by DNA hypomethylation at heterochromatin. It remains unclear why CDCA7-HELLS is sole nucleosome remodeling complex whose deficiency abrogates maintenance methylation. We here identify unique zinc-finger domain as an evolutionarily conserved hemimethylation-sensing zinc finger (HMZF) domain. Cryo–electron microscopy structural analysis CDCA7-nucleosome reveals that HMZF can recognize hemimethylated CpG in outward-facing major groove within core particle, whereas UHRF1, critical methyltransferase DNMT1, cannot. recruits to chromatin facilitates UHRF1-mediated H3 ubiquitylation associated with replication-uncoupled propose assists methylation on sensing otherwise inaccessible UHRF1 DNMT1.