Ionizing radiation‐induced long‐term expression of senescence markers in mice is independent of p53 and immune status

Abstract

SummaryExposure to IR has been shown to induce the formation of senescence markers, a phenotype that coincides with lifelong delayed repair and regeneration of irradiated tissues. We hypothesized that IR-induced senescence markers could persist long-term in vivo, possibly contributing to the permanent reduction in tissue functionality. Here, we show that mouse tissues exposed to a sublethal dose of IR display persistent (up to 45 weeks, the maximum time analyzed) DNA damage foci and increased p16 INK4a expression, two hallmarks of cellular senescence and aging. BrdU-labeling experiments revealed that IRinduced damaged cells are preferentially eliminated, at least partially, in a tissue-dependent manner. Unexpectedly, the accumulation of damaged cells was found to occur independent from the DNA damage response modulator p53, and from an intact immune system, as their levels were similar in wild-type and Rag2the latter being deficient in T, B, and NK cells. Together, our results provide compelling evidence that exposure to IR induces long-term expression of senescence markers in vivo, an effect that may contribute to the reduced tissue functionality observed in cancer survivors.

Ionizing radiation–induced expression of INK4a/ARF in murine bone marrow–derived stromal cell populations interferes with bone marrow homeostasis

“…Intriguingly, the expression of p16 INK4a and p19 ARF was not increased immediately after IR (data not shown), only 6-8 weeks later, a phenotype reminiscent of what we observed previously in other irradiated mouse tissues. 13,26 These results demonstrate that stromal cell populations derived from the BM microenvironment activate senescence markers after IR-induced DNA damage in vivo.…”

“…We chose this dose because it was shown previously to induce senescence markers in other mouse tissues and because it does not require BM transplantation for 100% of the mice to survive the irradiation. 26 Using a 2-step extraction procedure ( Figure 1A), we purified stromal cell populations from mice femurs and measured p16 INK4a and p19 ARF expression levels. The BM was first flushed from bones and stromal cells within this fraction were identified as BM-SCs.…”

p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes

“…INK4a expression) in several mouse tissues Le et al, 2010). HMGB1 was largely nuclear in unirradiated kidney cells, with <10% showing no or only faint nuclear staining (Fig.…”

DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion

“…7D). This delayed decline might reflect damage repair, clearance of damaged cells by the immune system (Ventura et al, 2007;Xue et al, 2007) and/or cell turnover (Le et al, 2010).…”