DNA damage response links calpain to cellular senescence.

Senescence represents an important barrier against cellular transformation. Here we show that CAPNS1 depletion impairs senescence induction both in BJ-ET H-Ras(v12) inducible human fibroblasts upon Ras induction and in HT1080 targeted to senescence by treatment with low doses of doxorubicin. We further show that CAPNS1 depletion is coupled to reduced levels of H2AX phosphorylation, not only in Ras(v12) induced BJ-ET fibroblasts, but also in a number of cellular systems upon genotoxic stress. In particular CAPNS1 depletion affects gamma-H2AX appearance or persistence in U2OS osteosarcoma cells 24 hours after MMC addition or UV light exposure; in HT1080 upon camptothecin treatment for 4 hours and 48 hours after addition of MMC; in MDA-MB-231, 24 hours after UV light exposure and 2 hours after bleomycin addition. Overall this study unveils a novel link between calpain, cellular senescence and DNA damage response.