The DNA damage signaling pathway is a critical mediator of oncogene-induced senescence |
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Authors: | Mallette Frédérick A Gaumont-Leclerc Marie-France Ferbeyre Gerardo |
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Affiliation: | Département de Biochimie, Université de Montréal, Montréal, Québec H3C 3J7, Canada. |
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Abstract: | Here we report that RNA interference against ATM inhibited p53 accumulation in cells expressing oncogenic STAT5 and cooperated with Rb inactivation to suppress STAT5A-induced senescence. Knocking down ATM was also effective to bypass E2F1-induced senescence and in combination with Rb inactivation, inhibited RasV12-induced senescence. Cells that senesced in response to ca-STAT5A or RasV12 accumulated DNA damage foci and activated ATM, ATR, Chk1, and Chk2, indicating that aberrant oncogene activation induces a DNA damage signaling response. Intriguingly, bypassing oncogene-induced senescence by inactivation of p53 and Rb did not eliminate the accumulation of oncogene-induced DNA damage foci (ODDI), suggesting a mechanism that may limit transformation in immortalized cells. |
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