Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2018 Jan 30;115(5):E876-E885. doi: 10.1073/pnas.1717509115. Epub 2018 Jan 16.

HELLS and CDCA7 comprise a bipartite nucleosome remodeling complex defective in ICF syndrome.

Author information

1
Laboratory of Chromosome and Cell Biology, The Rockefeller University, New York, NY 10065.
2
Department of Chemistry, Princeton University, Princeton, NJ 08544.
3
Cell Biology Center, Institute of Innovative Research, Tokyo Institute of Technology, 226-8503 Yokohama, Japan.
4
Laboratory of Chromosome and Cell Biology, The Rockefeller University, New York, NY 10065; funabih@rockefeller.edu.

Abstract

Mutations in CDCA7, the SNF2 family protein HELLS (LSH), or the DNA methyltransferase DNMT3b cause immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome. While it has been speculated that DNA methylation defects cause this disease, little is known about the molecular function of CDCA7 and its functional relationship to HELLS and DNMT3b. Systematic analysis of how the cell cycle, H3K9 methylation, and the mitotic kinase Aurora B affect proteomic profiles of chromatin in Xenopus egg extracts revealed that HELLS and CDCA7 form a stoichiometric complex on chromatin, in a manner sensitive to Aurora B. Although HELLS alone fails to remodel nucleosomes, we demonstrate that the HELLS-CDCA7 complex possesses nucleosome remodeling activity. Furthermore, CDCA7 is essential for loading HELLS onto chromatin, and CDCA7 harboring patient ICF mutations fails to recruit the complex to chromatin. Together, our study identifies a unique bipartite nucleosome remodeling complex where the functional remodeling activity is split between two proteins and thus delineates the defective pathway in ICF syndrome.

KEYWORDS:

HELLS; ICF; Xenopus; chromatin proteomics; nucleosome remodeling

PMID:
29339483
PMCID:
PMC5798369
DOI:
10.1073/pnas.1717509115
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center