Deficiency in the DNA repair protein ERCC1 triggers a link between senescence and apoptosis in human fibroblasts and mouse skin

Dong Eun Kim, Martijn E T Dollé, Wilbert P Vermeij, Akos Gyenis, Katharina Vogel, Jan H J Hoeijmakers, Christopher D Wiley, Albert R Davalos, Paul Hasty, Pierre-Yves Desprez, Judith Campisi

Research output: Contribution to journalArticlepeer-review

44 Citations (Scopus)


ERCC1 (excision repair cross complementing-group 1) is a mammalian endonuclease that incises the damaged strand of DNA during nucleotide excision repair and interstrand cross-link repair. Ercc1−/Δ mice, carrying one null and one hypomorphic Ercc1 allele, have been widely used to study aging due to accelerated aging phenotypes in numerous organs and their shortened lifespan. Ercc1−/Δ mice display combined features of human progeroid and cancer-prone syndromes. Although several studies report cellular senescence and apoptosis associated with the premature aging of Ercc1−/Δ mice, the link between these two processes and their physiological relevance in the phenotypes of Ercc1−/Δ mice are incompletely understood. Here, we show that ERCC1 depletion, both in cultured human fibroblasts and the skin of Ercc1−/Δ mice, initially induces cellular senescence and, importantly, increased expression of several SASP (senescence-associated secretory phenotype) factors. Cellular senescence induced by ERCC1 deficiency was dependent on activity of the p53 tumor-suppressor protein. In turn, TNFα secreted by senescent cells induced apoptosis, not only in neighboring ERCC1-deficient nonsenescent cells, but also cell autonomously in the senescent cells themselves. In addition, expression of the stem cell markers p63 and Lgr6 was significantly decreased in Ercc1−/Δ mouse skin, where the apoptotic cells are localized, compared to age-matched wild-type skin, possibly due to the apoptosis of stem cells. These data suggest that ERCC1-depleted cells become susceptible to apoptosis via TNFα secreted from neighboring senescent cells. We speculate that parts of the premature aging phenotypes and shortened health- or lifespan may be due to stem cell depletion through apoptosis promoted by senescent cells.
Original languageEnglish
Article numbere13072
Pages (from-to)e13072
JournalAging cell
Issue number3
Publication statusPublished - 1 Mar 2020


  • Animals
  • Apoptosis/genetics
  • Cells, Cultured
  • Cellular Senescence/genetics
  • DNA-Binding Proteins/deficiency
  • Endonucleases/deficiency
  • Fibroblasts/metabolism
  • Gene Knockdown Techniques
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Phenotype
  • Signal Transduction/genetics
  • Skin/metabolism
  • Stem Cells/metabolism
  • Transfection
  • Tumor Necrosis Factor-alpha/metabolism
  • Tumor Suppressor Protein p53/genetics


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