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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aurora Kinase B / metabolism
  • Cell Cycle
  • Chromatin / chemistry
  • Cluster Analysis
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA Helicases / genetics
  • DNA Helicases / metabolism*
  • DNA Methylation
  • DNA Methyltransferase 3B
  • Face / abnormalities*
  • HeLa Cells
  • Histones / metabolism
  • Humans
  • Immunologic Deficiency Syndromes / genetics*
  • Mutation*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Nucleosomes / chemistry
  • Ovum / metabolism
  • Peptides / chemistry
  • Primary Immunodeficiency Diseases
  • Protein Binding
  • Protein Domains
  • Proteomics
  • RNA Interference
  • Xenopus laevis


  • CDCA7 protein, human
  • Chromatin
  • Histones
  • Nuclear Proteins
  • Nucleosomes
  • Peptides
  • DNA (Cytosine-5-)-Methyltransferases
  • AURKB protein, human
  • Aurora Kinase B
  • DNA Helicases
  • HELLS protein, human

Supplementary concepts

  • Immunodeficiency syndrome, variable