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dc.contributor.authorKim, Dong Eun
dc.contributor.authorDollé, Martijn E T
dc.contributor.authorVermeij, Wilbert P
dc.contributor.authorGyenis, Akos
dc.contributor.authorVogel, Katharina
dc.contributor.authorHoeijmakers, Jan H J
dc.contributor.authorWiley, Christopher D
dc.contributor.authorDavalos, Albert R
dc.contributor.authorHasty, Paul
dc.contributor.authorDesprez, Pierre-Yves
dc.contributor.authorCampisi, Judith
dc.date.accessioned2019-12-01T15:57:17Z
dc.date.available2019-12-01T15:57:17Z
dc.date.issued2019-11-18
dc.identifier.issn1474-9726
dc.identifier.pmid31737985
dc.identifier.doi10.1111/acel.13072
dc.identifier.urihttp://hdl.handle.net/10029/623598
dc.description.abstractERCC1 (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.en_US
dc.language.isoenen_US
dc.subjectDNA damage repairen_US
dc.subjectagingen_US
dc.subjectcell deathen_US
dc.subjectsenescence-associated secretory phenotypeen_US
dc.subjecttumor necrosis factor αen_US
dc.titleDeficiency in the DNA repair protein ERCC1 triggers a link between senescence and apoptosis in human fibroblasts and mouse skin.en_US
dc.typeArticleen_US
dc.identifier.journalAging Cell 2019; 18:e13072en_US
dc.source.journaltitleAging cell


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