CDCA7 is an evolutionarily conserved hemimethylated DNA sensor in eukaryotes.
| Publication Type | Academic Article |
| Authors | Wassing I, Nishiyama A, Shikimachi R, Jia Q, Kikuchi A, Hiruta M, Sugimura K, Hong X, Chiba Y, Peng J, Jenness C, Nakanishi M, Zhao L, Arita K, Funabiki H |
| Journal | Sci Adv |
| Volume | 10 |
| Issue | 34 |
| Pagination | eadp5753 |
| Date Published | 08/23/2024 |
| ISSN | 2375-2548 |
| Keywords | DNA Methylation, Ubiquitin-Protein Ligases, Nucleosomes, CCAAT-Enhancer-Binding Proteins |
| Abstract | 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. |
| DOI | 10.1126/sciadv.adp5753 |
| PubMed ID | 39178260 |
| PubMed Central ID | PMC11343034 |