CDCA7 is a hemimethylated DNA adaptor for the nucleosome remodeler HELLS.

Publication Type	Preprint
Authors	Wassing I, 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
Journal	bioRxiv
Date Published	12/19/2023
ISSN	2692-8205
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.
DOI	10.1101/2023.12.19.572350
PubMed ID	38187757
PubMed Central ID	PMC10769307