| Summary: | p16<sup>I</sup><sup>nk4a</sup> is a tumor suppressor and a marker for cellular senescence. Previous studies have shown that p16<sup>I</sup><sup>nk4a</sup> plays an important role in the response to DNA damage signals caused by telomere dysfunction. In this study, we crossed <em>Wrn<sup>−/−</sup></em> and <em>p16<sup>I</sup><sup>nk4a−/−</sup></em> mice to knock out the <em>p16<sup>I</sup><sup>nk4a</sup></em> function in a Wrn null background. Growth curves showed that loss of p16<sup>I</sup><sup>nk4a</sup> could rescue the growth barriers that are observed in <em>Wrn</em><em><sup>−/−</sup></em> mouse embryonic fibroblasts (MEFs). By challenging the MEFs with the global genotoxin doxorubicin, we showed that<em> </em>loss of p16<sup>I</sup><sup>nk4a</sup><em> </em>did not dramatically affect the global DNA damage response of <em>Wrn<sup>−/−</sup></em> MEFs induced by doxorubicin. However, in response to telomere dysfunction initiated by the telomere damaging protein TRF2<sup>∆B∆M</sup>,<em> </em>loss of p16<sup>I</sup><sup>nk4a</sup> could partially overcome the DNA damage response by disabling p16<sup>I</sup><sup>nk4a</sup> up-regulation and reducing the accumulation of γ-H2AX that is observed in <em>Wrn<sup>−/−</sup></em> MEFs. Furthermore, in response to TRF2<sup>∆B∆M</sup> overexpression, <em>Wrn</em><em><sup>−/−</sup></em> MEFs senesced within several passages. In contrast, <em>p16<sup>I</sup></em><em><sup>nk4a−/−</sup></em> and <em>p16<sup>I</sup></em><em><sup>nk4a−/−</sup>Wrn<sup>−/−</sup></em> MEFs could continuously grow and lose expression of the exogenous TRF2<sup>∆B∆M</sup> in their late passages. In summary, our data suggest that in the context of telomere dysfunction, loss of p16<sup>I</sup><sup>nk4a</sup> function could prevent cells from senescence. These results shed light on the anti-aging strategy through regulation of p16<sup>Ink4a</sup> expression.
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