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PreprintCited by 31Epigenetics and DNA MethylationGenomics and Chromatin DynamicsChromatin Remodeling and Cancer

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CDCA7 is a hemimethylated DNA adaptor for the nucleosome remodeler HELLS

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Wassing, Isabel E., Nishiyama, Atsuya, Hiruta, Moeri, Jia, Qingyuan, Shikimachi, Reia, Kikuchi, Amika, Sugimura, Keita, Hong, Xin, Chiba, Yoshie, Peng, Junhui, Jenness, Christopher, Nakanishi, Makoto, Zhao, Li, Arita, Kyohei, Funabiki, Hironori·2023·Science Advances
DOI 10.1101/2023.12.19.572350PMC PMC11343034

Preprint — published as 10.1126/sciadv.adp5753 · Paper page

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Abstract

Mutations of the SNF2 family ATPase HELLS and its activator CDCA7 cause immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome, characterized by hypomethylation at heterochromatin. The unique zinc-finger domain, zf-4CXXC_R1, of CDCA7 is widely conserved across eukaryotes but is absent from species that lack HELLS and DNA methyltransferases, implying its specialized relation with methylated DNA. Here we demonstrate that zf-4CXXC_R1 acts as a hemimethylated DNA sensor. The zf-4CXXC_R1 domain of CDCA7 selectively binds to DNA with a hemimethylated CpG, but not unmethylated or fully methylated CpG, and ICF disease mutations eliminated this binding. CDCA7 and HELLS interact via their N-terminal alpha helices, through which HELLS is recruited to hemimethylated DNA. While placement of a hemimethylated CpG within the nucleosome core particle can hinder its recognition by CDCA7, cryo-EM structure analysis of the CDCA7-nucleosome complex suggests that zf-4CXXC_R1 recognizes a hemimethylated CpG in the major groove at linker DNA. Our study provides insights into how the CDCA7-HELLS nucleosome remodeling complex uniquely assists maintenance DNA methylation.

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Metadata

Authors
Wassing, I. E., Nishiyama, A., Hiruta, M., Jia, Q., Shikimachi, R., Kikuchi, A., Sugimura, K., Hong, X., Chiba, Y., Peng, J., Jenness, C., Nakanishi, M., Zhao, L., Arita, K., & Funabiki, H.
Affiliations
  • Rockefeller University (US)
  • Institute of Medical Science, The University of Tokyo (JP)
  • Yokohama City University (JP)
Corresponding author
  • Nishiyama, Atsuya
  • Arita, Kyohei
  • Funabiki, Hironori
ORCID
Venue
Science Advances
Publisher
openRxiv
Published
2023-12-19
Volume
10
Issue
34
Pages
eadp5753-eadp5753
ISSN
2375-2548 (ISSN-L)
DOI
10.1101/2023.12.19.572350
PMC
PMC11343034
OpenAlex
W4401834598
Cited by
31
References
1
Citations by year
2026: 9 · 2025: 18 · 2024: 4
FWCI
4.20
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Science Advances (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • Robertson Foundation
  • Ministry of Education, Culture, Sports, Science and Technology (JP19H05740)
  • National Institutes of Health
  • Japan Society for the Promotion of Science (24K02001, JP19H05741, 24K01967, 24K21950, JP19H05740)
  • RIKEN
  • National Institute of General Medical Sciences (R35GM132111, R35GM133780)
  • RIKEN Center for Biosystems Dynamics Research
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
CDCA7, HELLS, zinc finger, DNA methylation maintenance, nucleosome remodeling, UHRF1, DNMT1, heterochromatin, immunodeficiency, centromeric instability

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