Isabel 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
Published in Science Advances, Aug 2024 (Link)
Highlights:
- CDCA7 is an evolutionally conserved DNA hemimethylation sensor
- CDCA7 can recognize hemimethylated DNA on the nucleosome
- We identified the domain in CDCA7, sensing hemimethylated DNA
- CDCA7 can recruit HELLS to remodel chromatin to facilitate the maintenance of DNA methylation
Summary:
Mutations of the SNF2 family ATPase HELLS and its activator CDCA7 cause immunodeficiency, centromeric insta-bility, and facial anomalies syndrome, characterized by DNA hypomethylation at heterochromatin. It remains un-clear why CDCA7-HELLS is the sole nucleosome remodeling complex whose deficiency abrogates the maintenanceof DNA methylation. We here identify the unique zinc-finger domain of CDCA7 as an evolutionarily conservedhemimethylation-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-facingDNA major groove within the nucleosome core particle, whereas UHRF1, the critical activator of the maintenancemethyltransferase DNMT1, cannot. CDCA7 recruits HELLS to hemimethylated chromatin and facilitates UHRF1-mediated H3 ubiquitylation associated with replication-uncoupled maintenance DNA methylation. We proposethat the CDCA7-HELLS nucleosome remodeling complex assists the maintenance of DNA methylation on chroma-tin by sensing hemimethylated CpG that is otherwise inaccessible to UHRF1 and DNMT1.
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