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TitleCDCA7 is an evolutionarily conserved hemimethylated DNA sensor in eukaryotes.
Journal, issue, pagesSci Adv, Vol. 10, Issue 34, Page eadp5753, Year 2024
Publish dateAug 23, 2024
AuthorsIsabel E Wassing / Atsuya Nishiyama / Reia Shikimachi / Qingyuan Jia / Amika Kikuchi / Moeri Hiruta / Keita Sugimura / Xin Hong / Yoshie Chiba / Junhui Peng / Christopher Jenness / Makoto Nakanishi / Li Zhao / Kyohei Arita / Hironori Funabiki /
PubMed AbstractMutations of the SNF2 family ATPase HELLS and its activator CDCA7 cause immunodeficiency, centromeric instability, and facial anomalies syndrome, characterized by DNA hypomethylation at ...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.
External linksSci Adv / PubMed:39178260 / PubMed Central
MethodsEM (single particle)
Resolution3.0 - 4.83 Å
Structure data

EMDB-38198: hCDCA7 bound to nucleosome with hemimethylated CpG in 3'-linker DNA
Method: EM (single particle) / Resolution: 3.18 Å

EMDB-38199: hCDCA7 in complexed with linker DNA including hemimethylated CpG
Method: EM (single particle) / Resolution: 4.83 Å

39594

8yv8

EMDB-39594, PDB-8yv8:
Cryo-EM structure of CDCA7 bound to nucleosome including hemimethylated CpG site in Widom601 positioning sequence.
Method: EM (single particle) / Resolution: 3.0 Å

Chemicals

ChemComp-ZN:
Unknown entry

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsDNA BINDING PROTEIN / nucleosome / DNA methylation / CDCA7

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