RRC ID 81885
Author Shinkai A, Hashimoto H, Shimura C, Fujimoto H, Fukuda K, Horikoshi N, Okano M, Niwa H, Debler EW, Kurumizaka H, Shinkai Y.
Title The C-terminal 4CXXC-type zinc finger domain of CDCA7 recognizes hemimethylated DNA and modulates activities of chromatin remodeling enzyme HELLS.
Journal Nucleic Acids Res
Abstract The chromatin-remodeling enzyme helicase lymphoid-specific (HELLS) interacts with cell division cycle-associated 7 (CDCA7) on nucleosomes and is involved in the regulation of DNA methylation in higher organisms. Mutations in these genes cause immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome, which also results in DNA hypomethylation of satellite repeat regions. We investigated the functional domains of human CDCA7 in HELLS using several mutant CDCA7 proteins. The central region is critical for binding to HELLS, activation of ATPase, and nucleosome sliding activities of HELLS-CDCA7. The N-terminal region tends to inhibit ATPase activity. The C-terminal 4CXXC-type zinc finger domain contributes to CpG and hemimethylated CpG DNA preference for DNA-dependent HELLS-CDCA7 ATPase activity. Furthermore, CDCA7 showed a binding preference to DNA containing hemimethylated CpG, and replication-dependent pericentromeric heterochromatin foci formation of CDCA7 with HELLS was observed in mouse embryonic stem cells; however, all these phenotypes were lost in the case of an ICF syndrome mutant of CDCA7 mutated in the zinc finger domain. Thus, CDCA7 most likely plays a role in the recruitment of HELLS, activates its chromatin remodeling function, and efficiently induces DNA methylation, especially at hemimethylated replication sites.
Volume 52(17)
Pages 10194-10219
Published 2024-9-23
DOI 10.1093/nar/gkae677
PII 7731292
PMID 39142653
PMC PMC11417364
MeSH Adenosine Triphosphatases / genetics Adenosine Triphosphatases / metabolism Animals Cell Cycle Proteins / genetics Cell Cycle Proteins / metabolism Chromatin Assembly and Disassembly* CpG Islands / genetics DNA / genetics DNA / metabolism DNA Helicases* / chemistry DNA Helicases* / genetics DNA Helicases* / metabolism DNA Methylation* Face / abnormalities Heterochromatin / genetics Heterochromatin / metabolism Humans Immunologic Deficiency Syndromes / genetics Immunologic Deficiency Syndromes / metabolism Mice Mouse Embryonic Stem Cells / metabolism Mutation Nuclear Proteins Nucleosomes / genetics Nucleosomes / metabolism Primary Immunodeficiency Diseases / genetics Primary Immunodeficiency Diseases / metabolism Protein Binding Protein Domains Zinc Fingers*
Resource
Arabidopsis / Cultured plant cells, genes pda08628 pda19584