Figure 11.

Graphical summary. Our data suggest that SPHK2-generated S1P binds and stabilizes TERT involving its Asp⁶⁸⁴ residue via mimicking TERT phosphorylation at Ser⁹²¹, which protects telomere damage and results in delayed senescence and protection from apoptosis. Our data also suggest that targeting/inhibition of the SPHK2/S1P/telomerase axis results in telomere damage, which signals TCF21-dependent caspase-3 activation in cancer cells or immortalized MEFs, or p16-dependent senescence and accelerated aging phenotype in noncancerous primary lung fibroblasts, primary MEFs, or noncancerous tissues, such as testes, of subsequent generations of SphK2^−/− mice. Thus, these data reveal that p16 abundance induces senescence and prevents caspase-3–dependent apoptosis in response to telomere damage via p16–caspase-3 interaction in response to targeting the SPHK2/S1P/telomerase axis.