Pontin-deficiency causes senescence in fibroblast cells and epidermal keratinocytes but induces apoptosis in cancer cells

Highlights

• Pontin-deficiency induced cellular senescence in mouse and human fibroblasts.

• Pontin deletion in epidermal keratinocytes led to senescence in vivo.

• Pontin-deficiency caused a spontaneous DNA damage response.

• Pontin depletion in several cancer cells caused apoptosis rather than senescence.

Abstract

Pontin, a member of the AAA+ ATPase family, plays important roles in a variety of cellular processes, including transcription regulation, DNA damage response, telomerase activity, and cellular transformation. In the previous studies, Pontin deletion in mice was lethal to embryos. Here, we demonstrate that the depletion of Pontin induced cellular senescence in mouse and human fibroblasts as well as in mouse epidermal keratinocytes. Fibroblast cells with Pontin depletion exhibited a defect in cell proliferation without showing apoptosis. Instead, they exhibited senescence-associated phenotypes including increased senescence-associated-β-galactosidase activity, elevated levels of p16^INK4, and senescence-associated secretory phenotypes. Furthermore, conditional deletion of the Pontin gene in epidermal keratinocytes led to abnormal epidermal stratification, which was accompanied by the induction of senescence in Pontin-lacking cells. We found that Pontin depletion induced a spontaneous DNA damage response, which may be a cause of senescence. Contrary to the behavior of normal cells, Pontin depletion in several cancer cells caused apoptotic cell death without exhibiting senescence phenotypes.