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Vol. 17, Issue 4, 1583-1592, April 2006

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DNA Damage Signaling and p53-dependent Senescence after Prolonged -Interferon Stimulation

Département de Biochimie, Université de Montréal, Montréal, Québec H3C 3J7, Canada

Submitted September 15, 2005; Revised January 10, 2006; Accepted January 18, 2006
Monitoring Editor: Gerard Evan

Interferons are cytokines with potent antiviral and antiproliferative activities. We report that although a transient exposure to -interferon induces a reversible cell cycle arrest, a sustained treatment triggers a p53-dependent senescence program. -Interferon switched on p53 in two steps. First, it induced the acetylation of p53 at lysine 320 and its dephosphorylation at serine 392 but not p53 activity. Later on, it triggered a DNA signaling pathway, the phosphorylation of p53 at serine 15 and its transcriptional activity. In agreement, -interferon–treated cells accumulated -H2AX foci and phosphorylated forms of ATM and CHK2. The DNA damage signaling pathway was activated by an increase in reactive oxygen species (ROS) induced by interferon and was inhibited by the antioxidant N-acetyl cysteine. More important, RNA interference against ATM inhibited p53 phosphorylation at serine 15, p53 activity and senescence in response to -interferon. -Interferon–induced senescence was more efficient in cells expressing either, p53, or constitutive allele of ERK2 or RasV12. Hence, -interferon–induced senescence targets preferentially cells with premalignant changes.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Gerardo Ferbeyre (g.ferbeyre{at}umontreal.ca).

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