2. Academic Validation
  3. The C-terminal 4CXXC-type zinc finger domain of CDCA7 recognizes hemimethylated DNA and modulates activities of chromatin remodeling enzyme HELLS

The C-terminal 4CXXC-type zinc finger domain of CDCA7 recognizes hemimethylated DNA and modulates activities of chromatin remodeling enzyme HELLS

  • Nucleic Acids Res. 2024 Aug 15:gkae677. doi: 10.1093/nar/gkae677.
Akeo Shinkai 1,  Hideharu Hashimoto 2,  Chikako Shimura 1,  Hiroaki Fujimoto 1 3,  Kei Fukuda 4,  Naoki Horikoshi 5,  Masaki Okano 6,  Hitoshi Niwa 6,  Erik W Debler 2,  Hitoshi Kurumizaka 5,  Yoichi Shinkai 1 3
Affiliations

Affiliations

  • 1 Cellular Memory Laboratory, RIKEN Cluster for Pioneering Research, Wako City, Saitama 351-0198, Japan.
  • 2 Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
  • 3 Division of Life Science, Graduate School of Science & Engineering, Saitama University, Shimo-Ohkubo 255, Sakura Ward, Saitama City, Saitama 338-8570, Japan.
  • 4 Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi 400-8510, Japan.
  • 5 Laboratory of Chromatin Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
  • 6 Department of Pluripotent Stem Cell Biology, IMEG, Kumamoto university, Honjo 2-2-1, Chuo-ku, Kumamoto, Kumamoto 860-0811, Japan.
PMID: 39142653 DOI: 10.1093/nar/gkae677
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.

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