Deficiency of the DNA repair protein ERCC1 triggers a connection between senescence, apoptosis and human fibroblasts in mouse skin
ERCC1 is a mammalian RNA endonuclease which incises damaged DNA strands during interstrand cross-link and nucleotide repair. Ercc1 mice carrying one null allele and one hypomorphic Ercc1 have been used extensively to study aging because of their shorter lifespan and accelerated aging in many organs. Ercc1/D mice show features that are similar to human cancer-prone and progeroid syndromes. The link between cellular senescence, apoptosis and premature aging in Ercc1/D mice is not fully understood. Here, we show that ERCC1 depletion, both in cultured human fibroblasts and the skin of Ercc1-/D mice, initially induces cellular senescence and, importantly, increased expression of several SASP (senescence-associated secretory phenotype) factors. The cellular senescence induced in ERCC1-deficient cells was dependent on the activity of p53, a tumor suppressor protein. TNFa, secreted from senescent cell, induced apoptosis in ERCC1 deficient cells as well as in senescent cell itself. The expression of the stem-cell markers Lgr6 and p63 was also significantly reduced in Ercc1/D mouse skin where the apoptotic cell clusters are located, as compared to wild-type skin of an age-matched age. This could be due to stem-cell apoptosis. These results suggest that ERCC1 depleted cells are susceptible to apoptosis by TNFa released from nearby senescent cell. We hypothesize that stem cell depletion may contribute to premature aging and shorter health or lifespan.
Source:
https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13072?campaign=wolearlyview
