The C-terminal 4CXXC-type Zinc Finger Domain of CDCA7 Recognizes Hemimethylated DNA and Modulates Activities of Chromatin Remodeling Enzyme HELLS

Authors

Akeo Shinkai
Hideharu Hashimoto, Thomas Jefferson UniversityFollow
Chikako Shimura
Hiroaki Fujimoto
Kei Fukuda
Naoki Horikoshi
Masaki Okano
Hitoshi Niwa
Erik W Debler
Hitoshi Kurumizaka
Yoichi Shinkai

Document Type

Article

Publication Date

9-23-2024

Comments

This article is the author's final published version in Nucleic Acids Research, Volume 52, Issue 17, September 2024, pages 10194-10219.

The published version is available at https://doi.org/10.1093/nar/gkae677.

Copyright © 2024 The Author(s).

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.

Recommended Citation

Shinkai, Akeo; Hashimoto, Hideharu; Shimura, Chikako; Fujimoto, Hiroaki; Fukuda, Kei; Horikoshi, Naoki; Okano, Masaki; Niwa, Hitoshi; Debler, Erik W; Kurumizaka, Hitoshi; and Shinkai, Yoichi, "The C-terminal 4CXXC-type Zinc Finger Domain of CDCA7 Recognizes Hemimethylated DNA and Modulates Activities of Chromatin Remodeling Enzyme HELLS" (2024). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 267.
https://jdc.jefferson.edu/bmpfp/267

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License

PubMed ID

39142653

Language

English