Deficiency in the DNA repair protein ERCC1 triggers a link between senescence and apoptosis in human fibroblasts and mouse skin
Autor: | Akos Gyenis, Paul Hasty, Christopher D. Wiley, Martijn E.T. Dollé, Pierre Yves Desprez, Katharina Vogel, Dong Eun Kim, Jan H.J. Hoeijmakers, Judith Campisi, Albert R. Davalos, Wilbert P. Vermeij |
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Přispěvatelé: | Molecular Genetics |
Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Premature aging Senescence Programmed cell death Apoptosis Mice Transgenic Biology Stem cell marker Transfection tumor necrosis factor α Medical and Health Sciences 03 medical and health sciences Mice 0302 clinical medicine Animals Humans DNA damage repair Cells Cultured Cellular Senescence Skin Tumor Necrosis Factor-alpha Stem Cells aging Cell Biology Original Articles Biological Sciences Fibroblasts Endonucleases Cell biology DNA-Binding Proteins Mice Inbred C57BL 030104 developmental biology Phenotype cell death Gene Knockdown Techniques senescence-associated secretory phenotype Original Article Stem cell ERCC1 Tumor Suppressor Protein p53 senescence‐associated secretory phenotype 030217 neurology & neurosurgery Developmental Biology Nucleotide excision repair Signal Transduction |
Zdroj: | Aging Cell Aging Cell, 19. Wiley-Blackwell Publishing Ltd Aging cell, vol 19, iss 3 |
ISSN: | 1474-9726 1474-9718 |
Popis: | 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. ERCC1‐depleted cells become susceptible to apoptosis via TNFalpha secreted from neighboring senescent cells. Part of the premature aging phenotypes in ERCC1‐deficient mice may be due to stem cell depletion through apoptosis promoted by cellular senescence. |
Databáze: | OpenAIRE |
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