TY - JOUR
T1 - Deficiency in the DNA repair protein ERCC1 triggers a link between senescence and apoptosis in human fibroblasts and mouse skin
AU - Kim, Dong Eun
AU - Dollé, Martijn E.T.
AU - Vermeij, Wilbert P.
AU - Gyenis, Akos
AU - Vogel, Katharina
AU - Hoeijmakers, Jan H.J.
AU - Wiley, Christopher D.
AU - Davalos, Albert R.
AU - Hasty, Paul
AU - Desprez, Pierre Yves
AU - Campisi, Judith
N1 - Funding Information:
We thank Renata Brandt, Sander Barnhoorn and the animal caretakers for general assistance with mouse experiments, Dr. Amit Sharma for helpful comments, and Dr. Jan Vijg for critical reading of the manuscript. This work was supported by the Swiss National Foundation Mobility Postdoc Fellowship, NIH grants AG009909 and AG017242, European Research Council Advanced Grants Dam2Age, the KWO Dutch Cancer Society (5030), and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Projektnummer 73111208 ‐ SFB 829.
Funding Information:
We thank Renata Brandt, Sander Barnhoorn and the animal caretakers for general assistance with mouse experiments, Dr. Amit Sharma for helpful comments, and Dr. Jan Vijg for critical reading of the manuscript. This work was supported by the Swiss National Foundation Mobility Postdoc Fellowship, NIH grants AG009909 and AG017242, European Research Council Advanced Grants Dam2Age, the KWO Dutch Cancer Society (5030), and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Projektnummer 73111208 - SFB 829.
Publisher Copyright:
© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
PY - 2020/3/1
Y1 - 2020/3/1
N2 - 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.
AB - 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.
KW - DNA damage repair
KW - aging
KW - cell death
KW - senescence-associated secretory phenotype
KW - tumor necrosis factor α
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UR - http://www.scopus.com/inward/citedby.url?scp=85075164227&partnerID=8YFLogxK
U2 - 10.1111/acel.13072
DO - 10.1111/acel.13072
M3 - Article
C2 - 31737985
AN - SCOPUS:85075164227
SN - 1474-9718
VL - 19
JO - Aging Cell
JF - Aging Cell
IS - 3
M1 - e13072
ER -