The DNA damage signaling pathway is a critical mediator of oncogene-induced senescence

  1. Frédérick A. Mallette,
  2. Marie-France Gaumont-Leclerc, and
  3. Gerardo Ferbeyre1
  1. Département de Biochimie, Université de Montréal, Montréal, Québec H3C 3J7, Canada

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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