Deficiency in the DNA repair protein ERCC1 triggers a link between senescence and apoptosis in human fibroblasts and mouse skin.
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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-/? 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-/? 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-/? mice, the link between these two processes and their physiological relevance in the phenotypes of Ercc1-/? mice are incompletely understood. Here, we show that ERCC1 depletion, both in cultured human fibroblasts and the skin of Ercc1-/? 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? 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-/? 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? 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.
SUBMITTER: Kim DE
PROVIDER: S-EPMC7059167 | biostudies-literature | 2020 Mar
REPOSITORIES: biostudies-literature
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