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

Alice De Castro,Eva Hattinger,Eric Kenneth Parkinson,Fay Minty,Ronald Wolf

doi:10.1186/2046-2395-3-8

Abstract

BackgroundReplicative 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).ResultsWe 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 (p14ARF), CDKN2A (p16INK4A) 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 p16INK4A and p53 and to a lesser extent by p14ARF.ConclusionsOur 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.

Highlights

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)
Markers of keratinocyte telomere dysfunction are not induced by DNA double strand breaks In order to test whether the small DDR observed following keratinocyte telomere uncapping or shortening [28] was responsible for the induction of HIST2H2BE, ICEBERG, HOPX and S100A7, we exposed normal human keratinocytes to 2, 10 or 20 gray of ionising radiation
The 2-gray dose did not reduce the levels of cyclin A2 and cyclin D1 transcript [32] (Figure 1b) as these transcripts take longer than 6 h to reduce and did not induce the early stages of terminal differentiation as assessed by involucrin transcript (Figure 1b)

Summary

Introduction

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). Telomeres will shorten when cells divide in the absence of telomerase due to either the end replication problem [4,7,8], exonuclease digestion [9] or, in some circumstances, oxidative damage [10,11]. This culminates in the telomere being perceived as a DSB [12] and most senescent cells mount a significant DDR [13]. Telomerase has been reported to remove the IrrDSBs at telomeres, but it is not clear whether this property is related to its canonical telomere-lengthening function [18]

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