Pseudo-DNA damage response in senescent cells

Abstract

Cellular senescence is currently viewed as a response to DNA damage. In this report, we showed that non-damaging agents such as sodium butyrate-induced p21 and ectopic expression of either p21 or p16 cause cellular senescence without detectable DNA breaks. Nevertheless, senescent cells displayed components of DNA damage response (DDR) such as γH2AX foci and uniform nuclear staining for p-ATM. Importantly, there was no accumulation of 53BP1 in γH2AX foci of senescent cells. Consistently, comet assay failed to detect DNA damage. Rapamycin, an inhibitor of mTOR, which was shown to suppress cellular senescence, decreased γH2AX foci formation. Thus, cellular senescence leads to activation of atypical DDR without detectable DNA damage. Pseudo-DDR may be a marker of general over-activation of senescent cells.

ATM-dependent E2F1 accumulation in the nucleolus is an indicator of ribosomal stress in early response to DNA damage

“…45 Rapamycin may also prevent the formation of ATM-phosphorylated H2AX (γ-H2AX), thereby suppressing mTOR-dependent pseudo-DNA damage response in senescent cells. 46 These findings support the notion that mTOR signaling is involved in cell stresses including ribosomal stress. 12 The mTOR kinase therefore may cooperate with E2F1 under ribosomal stress.…”

A set of miRNAs participates in the cellular senescence program in human diploid fibroblasts

“…Thus, overexpression of the five miRNAs favored DNA damage, and not solely DDR (gH2AX), which can also occur in the absence of DNA damage (pseudo-DDR). 24 Finally, we showed that the mTOR pathway was an essential driver of senescence induced by senescence-associated miRNAs as SA-b-gal staining was significantly reduced by treatment with rapamycin. [20][21][22] Of note, our preliminary observations, by studying the expression levels of the senescence-inducing miRNAs in human skin broblasts from young (age [17][18][19][20][21][22][23][24][25] or old (age 89-94) donors, show that the highest expression levels of miR-376a* and miR-494 were found in one old donor cell line, and expression of miR-486-5p was on average two-fold higher in old with respect to young cells.…”

The STAT3-IGFBP5 axis is critical for IL-6/gp130-induced premature senescence in human fibroblasts

“…[37][38][39][40][41] Therefore, in addition to the critical role of the STAT3-IGFBP5 axis in the IL-6-induced premature senescence, mTOR activity caused by serum growth factors and added IL-6 together with secreted factors during the course is likely to contribute to the premature senescence. However, our preliminary experiments showed that TIG3 cells with a chimeric receptor with truncated gp130 containing only the YRHQ motif, which activates only the STAT3 pathway without activating the ERK1/2 or PI3K/AKT/mTOR pathways, induced premature senescence in TIG3 cells at the extent comparable with that shown in IL-6/sIL-6R stimulation (unpublished data, Kojima H and Nakajima K).…”