ERCC1-XPF cooperates with CTCF and cohesin to facilitate the developmental silencing of imprinted genes

Nat Cell Biol. 2017 May;19(5):421-432. doi: 10.1038/ncb3499. Epub 2017 Apr 3.

Abstract

Inborn defects in DNA repair are associated with complex developmental disorders whose causal mechanisms are poorly understood. Using an in vivo biotinylation tagging approach in mice, we show that the nucleotide excision repair (NER) structure-specific endonuclease ERCC1-XPF complex interacts with the insulator binding protein CTCF, the cohesin subunits SMC1A and SMC3 and with MBD2; the factors co-localize with ATRX at the promoters and control regions (ICRs) of imprinted genes during postnatal hepatic development. Loss of Ercc1 or exposure to MMC triggers the localization of CTCF to heterochromatin, the dissociation of the CTCF-cohesin complex and ATRX from promoters and ICRs, altered histone marks and the aberrant developmental expression of imprinted genes without altering DNA methylation. We propose that ERCC1-XPF cooperates with CTCF and cohesin to facilitate the developmental silencing of imprinted genes and that persistent DNA damage triggers chromatin changes that affect gene expression programs associated with NER disorders.

MeSH terms

  • Age Factors
  • Animals
  • Animals, Newborn
  • CCCTC-Binding Factor
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cells, Cultured
  • Chondroitin Sulfate Proteoglycans / genetics
  • Chondroitin Sulfate Proteoglycans / metabolism
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Coculture Techniques
  • DNA Damage
  • DNA Helicases / genetics
  • DNA Helicases / metabolism
  • DNA Repair*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Endonucleases / genetics
  • Endonucleases / metabolism*
  • Fibroblasts / enzymology
  • Gene Expression Regulation, Developmental
  • Gene Silencing*
  • Genomic Imprinting*
  • Genotype
  • Histones / metabolism
  • Liver / enzymology
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Phenotype
  • Promoter Regions, Genetic
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • X-linked Nuclear Protein

Substances

  • CCCTC-Binding Factor
  • Cell Cycle Proteins
  • Chondroitin Sulfate Proteoglycans
  • Chromosomal Proteins, Non-Histone
  • Cspg6 protein, mouse
  • Ctcf protein, mouse
  • DNA-Binding Proteins
  • Histones
  • Mbd2 protein, mouse
  • Nuclear Proteins
  • Repressor Proteins
  • cohesins
  • structural maintenance of chromosome protein 1
  • xeroderma pigmentosum group F protein
  • Endonucleases
  • Ercc1 protein, mouse
  • DNA Helicases
  • Atrx protein, mouse
  • X-linked Nuclear Protein