SRC activation skews cell fate from apoptosis to senescence

Abstract Cells responding to DNA damage implement complex adaptive programs that often culminate in two distinct outcomes: apoptosis or senescence. To systematically identify factors driving each response, we analyzed human IMR-90 fibroblasts exposed to increasing doses of the genotoxin etoposide and identified SRC as a key kinase contributing to this dichotomous decision. SRC was activated by low (50 μM) etoposide but not by high (200 μM) etoposide levels. With low DNA damage, SRC-mediated activation of p38 critically promoted cell survival and senescence, and increased pro-survival BCL2L2 levels, while SRC-mediated repression of p53 prevented a rise in pro-apoptotic PUMA levels. With high DNA damage, SRC was not activated, leading to elevation of p53, inhibition of p38, and apoptosis. In mice exposed to DNA damage, pharmacologic inhibition of SRC prevented tissue accumulation of senescent cells. We propose that inhibiting SRC could be exploited to induce senescent-cell apoptosis in tissues to improve health outcomes.