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Background  Replicative senescence is preceded by loss of repeat sequences of DNA from the telomeres that eventually leads to telomere dysfunction, the accumulation of irreparable DNA double strand breaks and a DNA damage response (DDR). However, we have previously reported that whilst telomere dysfunction in human keratinocytes is associated with a permanent cell cycle arrest, the DDR was very weak and transcriptional profiling also revealed several molecules normally associated with keratinocytes terminal differentiation, including S100A7 (psoriasin).    Results  We show here that  S100A7  and the closely related  S100A15  (koebnerisin) are not induced by repairable or irreparable DSBs, ruling out the hypotheses that these genes are induced either by the low DDR observed or by non-specific cell cycle arrest. We next tested whether  S100A7  was induced by the cell cycle effectors  ARF  (p14 ARF ),  CDKN2A  (p16 INK4A ) and  TP53  (p53) and found that, although all induced a similar level of acute and permanent cell cycle arrest to telomere dysfunction, none induced  S100A7  (except p53 over-expression at high levels), showing that cell cycle arrest is not sufficient for its induction. The closely related transcript  S100A15  was also upregulated by telomere dysfunction, to a similar extent by p16 INK4A  and p53 and to a lesser extent by p14 ARF .    Conclusions  Our results show that mere cell cycle arrest, the upregulation of senescence-associated cell cycle effectors and DNA damage are not sufficient for the induction of the  S100  transcripts; they further suggest that whilst the induction of  S100A15  expression is linked to both telomere-dependent and -independent senescence,  S100A7  expression is specifically associated with telomere-dependent senescence in normal keratinocytes. As both S100A7 and S100A15 are secreted proteins, they may find utility in the early detection of human keratinocyte telomere dysfunction and senescence.

longevity and healthspan

The secreted protein S100A7 (psoriasin) is induced by telomere dysfunction in human keratinocytes independently of a DNA damage response and cell cycle regulators