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

Aging cell 2020 Mar

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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. © 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Citation

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. Deficiency in the DNA repair protein ERCC1 triggers a link between senescence and apoptosis in human fibroblasts and mouse skin. Aging cell. 2020 Mar;19(3):e13072