Kim, Dong Eun, Dolle, Martijn E. T., Vermeij, Wilbert P., Gyenis, Akos, Vogel, Katharina, Hoeijmakers, Jan H. J., Wiley, Christopher D., Davalos, Albert R., Hasty, Paul, Desprez, Pierre-Yves and Campisi, Judith (2020). Deficiency in the DNA repair protein ERCC1 triggers a link between senescence and apoptosis in human fibroblasts and mouse skin. Aging Cell, 19 (3). HOBOKEN: WILEY. ISSN 1474-9726
Full text not available from this repository.Abstract
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(-/Delta) 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(-/Delta) 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(-/Delta) mice, the link between these two processes and their physiological relevance in the phenotypes of Ercc1(-/Delta) mice are incompletely understood. Here, we show that ERCC1 depletion, both in cultured human fibroblasts and the skin of Ercc1(-/Delta) 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, TNF alpha 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(-/Delta) 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 TNF alpha 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.
Item Type: | Journal Article | ||||||||||||||||||||||||||||||||||||||||||||||||
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URN: | urn:nbn:de:hbz:38-127443 | ||||||||||||||||||||||||||||||||||||||||||||||||
DOI: | 10.1111/acel.13072 | ||||||||||||||||||||||||||||||||||||||||||||||||
Journal or Publication Title: | Aging Cell | ||||||||||||||||||||||||||||||||||||||||||||||||
Volume: | 19 | ||||||||||||||||||||||||||||||||||||||||||||||||
Number: | 3 | ||||||||||||||||||||||||||||||||||||||||||||||||
Date: | 2020 | ||||||||||||||||||||||||||||||||||||||||||||||||
Publisher: | WILEY | ||||||||||||||||||||||||||||||||||||||||||||||||
Place of Publication: | HOBOKEN | ||||||||||||||||||||||||||||||||||||||||||||||||
ISSN: | 1474-9726 | ||||||||||||||||||||||||||||||||||||||||||||||||
Language: | English | ||||||||||||||||||||||||||||||||||||||||||||||||
Faculty: | Unspecified | ||||||||||||||||||||||||||||||||||||||||||||||||
Divisions: | Unspecified | ||||||||||||||||||||||||||||||||||||||||||||||||
Subjects: | no entry | ||||||||||||||||||||||||||||||||||||||||||||||||
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Refereed: | Yes | ||||||||||||||||||||||||||||||||||||||||||||||||
URI: | http://kups.ub.uni-koeln.de/id/eprint/12744 |
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