Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Nikolaou Plastira 100, 70013 Heraklion, Crete, Greece.
Department of Biology, University of Crete, Vassilika Vouton, GR71409 Heraklion, Crete, Greece.
Nat Cell Biol. 2017 May;19(5):421-432. doi: 10.1038/ncb3499. Epub 2017 Apr 3.
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.
先天性 DNA 修复缺陷与复杂的发育障碍有关，但其因果机制尚不清楚。我们利用小鼠体内生物素标记标记方法，发现核苷酸切除修复（NER）结构特异性内切酶 ERCC1-XPF 复合物与绝缘子结合蛋白 CTCF、黏连蛋白亚基 SMC1A 和 SMC3 以及 MBD2 相互作用；这些因子在出生后肝发育过程中与 ATRX 一起定位于印迹基因的启动子和调控区（ICRs）。Ercc1 的缺失或 MMC 的暴露会触发 CTCF 向异染色质的定位、CTCF-黏连蛋白复合物以及 ATRX 从启动子和 ICRs 的解离、组蛋白标记的改变以及印迹基因的异常发育表达，而不会改变 DNA 甲基化。我们提出 ERCC1-XPF 与 CTCF 和黏连蛋白合作，促进印迹基因的发育沉默，持续的 DNA 损伤会引发染色质变化，从而影响与 NER 障碍相关的基因表达程序。
