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Vol. 20, Issue 7, 1891-1902, April 1, 2009

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DNA Damage Triggers p21^WAF1-dependent Emi1 Down-Regulation That Maintains G2 Arrest

Jinho Lee^*,, Jin Ah Kim^*,, Valerie Barbier, Arun Fotedar, and Rati Fotedar^*,

*Institut de Biologie Structurale J.-P. Ebel, F38027 Grenoble, France; and Sidney Kimmel Cancer Center, San Diego CA 92121

Submitted August 8, 2008; Revised January 30, 2009; Accepted February 3, 2009
Monitoring Editor: Daniel J. Lew

Several regulatory proteins control cell cycle progression. These include Emi1, an anaphase-promoting complex (APC) inhibitor whose destruction controls progression through mitosis to G1, and p21^WAF1, a cyclin-dependent kinase (CDK) inhibitor activated by DNA damage. We have analyzed the role of p21^WAF1 in G2-M phase checkpoint control and in prevention of polyploidy after DNA damage. After DNA damage, p21^+/+ cells stably arrest in G2, whereas p21^–/– cells ultimately progress into mitosis. We report that p21 down-regulates Emi1 in cells arrested in G2 by DNA damage. This down-regulation contributes to APC activation and results in the degradation of key mitotic proteins including cyclins A2 and B1 in p21^+/+ cells. Inactivation of APC in irradiated p21^+/+ cells can overcome the G2 arrest. siRNA-mediated Emi1 down-regulation prevents irradiated p21^–/– cells from entering mitosis, whereas concomitant down-regulation of APC activity counteracts this effect. Our results demonstrate that Emi1 down-regulation and APC activation leads to stable p21-dependent G2 arrest after DNA damage. This is the first demonstration that Emi1 regulation plays a role in the G2 DNA damage checkpoint. Further, our work identifies a new p21-dependent mechanism to maintain G2 arrest after DNA damage.

Address correspondence to: Rati Fotedar (rfotedar{at}skcc.org)

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