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

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.