Loss of p16(Ink4a) function rescues cellular senescence induced by telomere dysfunction.

p16(Ink4a) is a tumor suppressor and a marker for cellular senescence. Previous studies have shown that p16(Ink4a) plays an important role in the response to DNA damage signals caused by telomere dysfunction. In this study, we crossed Wrn(-/-) and p16(Ink4a-/-) mice to knock out the p16(Ink4a) function in a Wrn null background. Growth curves showed that loss of p16(Ink4a) could rescue the growth barriers that are observed in Wrn(-/-) mouse embryonic fibroblasts (MEFs). By challenging the MEFs with the global genotoxin doxorubicin, we showed that loss of p16(Ink4a) did not dramatically affect the global DNA damage response of Wrn(-/-) MEFs induced by doxorubicin. However, in response to telomere dysfunction initiated by the telomere damaging protein TRF2(ΔBΔM), loss of p16(Ink4a) could partially overcome the DNA damage response by disabling p16(Ink4a) up-regulation and reducing the accumulation of γ-H2AX that is observed in Wrn(-/-) MEFs. Furthermore, in response to TRF2(ΔBΔM) overexpression, Wrn(-/-) MEFs senesced within several passages. In contrast, p16(Ink4a-/-) and p16(Ink4a-/-)Wrn(-/-) MEFs could continuously grow and lose expression of the exogenous TRF2(ΔBΔM) in their late passages. In summary, our data suggest that in the context of telomere dysfunction, loss of p16(Ink4a) function could prevent cells from senescence. These results shed light on the anti-aging strategy through regulation of p16(Ink4a) expression.