Abstract
p53 plays a central role in tumor suppression. It does so by inducing anti-proliferative processes as a response to various tumor-promoting stresses. p53 is regulated by the ubiquitin ligase Mdm2. The optimal function of Mdm2 requires Daxx, which stabilizes Mdm2 through the deubiquitinase Hausp/USP7 and also directly promotes Mdm2’s ubiquitin ligase activity towards p53. The Daxx-Mdm2 interaction is disrupted upon DNA damage. However, both the mechanisms and the consequence of the Daxx-Mdm2 dissociation are not understood. Here we show that upon DNA damage Daxx is phosphorylated in a manner that is dependent on ATM, a member of the PI 3-kinase family that orchestrates the DNA damage response. The main phosphorylation site of Daxx is identified to be Ser564, which is a direct target of ATM. Phosphorylation of endogenous Daxx at Ser564 occurs rapidly during the DNA damage response and precedes p53 activation. Blockage of this phosphorylation event prevents the separation of Daxx from Mdm2, stabilizes Mdm2, and inhibits DNA damage-induced p53 activation. These results suggest that phosphorylation of Daxx by ATM upon DNA damage disrupts the Daxx-Mdm2 interaction and facilitates p53 activation.
Highlights
Cells carrying an activated oncogene, damaged genome, or other cancer-promoting alterations are normally prevented from replicating through an elaborate tumor suppression network
A central hub of this network is p53 [1,2]. p53 is a transcription factor that controls the expression of a large number of genes involved in cell cycle arrest, apoptosis, and senescence [3,4]. p53 has transcription-independent functions in the induction of cytochrome c release from mitochondria [5,6] and the inhibition of glucose metabolism and biosynthesis [7,8]
The inhibition of Mdm2 under stress conditions enables p53 to stabilize. p53 stabilization induced by DNA damage is dependent on ATM [12], which orchestrates the cellular response to DNA double strand breaks by phosphorylating a wide range of substrates
Summary
Cells carrying an activated oncogene, damaged genome, or other cancer-promoting alterations are normally prevented from replicating through an elaborate tumor suppression network. P53 degradation is largely mediated by Mdm (mouse double minute, known as Hdm in humans), a RING domain-containing E3 ubiquitin ligase [9,10,11]. P53 stabilization induced by DNA damage is dependent on ATM (ataxia telangiectasia mutated) [12], which orchestrates the cellular response to DNA double strand breaks by phosphorylating a wide range of substrates. Targeted mutations of one or both of the corresponding sites in murine p53 led to only modest defects in p53 activation [17,18,19], indicating that other mechanisms downstream of ATM may contribute to inactivation of Mdm
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