The p53 tumor suppressor protein has a major role in protecting genome 
integrity. Under normal circumstances Mdmx and Mdm2 control the activity of p53. 
Both proteins inhibit the transcriptional regulation by p53, while Mdm2 also 
functions as an E3 ubiquitin ligase to target both p53 and Mdmx for proteasomal 
degradation. HAUSP counteracts the destabilizing effect of Mdm2 by direct 
deubiquitination of p53. Subsequently, HAUSP was shown to deubiquitinate Mdm2 
and Mdmx, thereby stabilizing these proteins. The ATM protein kinase is a key 
regulator of the p53 pathway in response to double strand breaks (DSBs) in the 
DNA. ATM fine-tunes p53's response to DNA damage by directly phosphorylating it, 
by regulating additional post-translational modifications of this protein, and 
by affecting two p53 regulators: Mdm2 and Mdmx. ATM directly and indirectly 
induces Mdm2 and Mdmx phosphorylation, resulting in decreased activity and 
stability of these proteins. We recently provided a mechanism for the reduced 
stability of Mdm2 and Mdmx by showing that ATM-dependent phosphorylation lowers 
their affinity for the deubiquitinating enzyme HAUSP. Altogether, the emerging 
picture portrays an elaborate, but fine-tuned, ATM-mediated control of p53 
activation and stabilization following DNA damage. Further insight into the 
mechanism by which ATM switches the interactions between HAUSP, Mdmx, Mdm2 and 
p53, to favor p53 activation may offer new tools for therapeutic intervention in 
the p53 pathway for cancer treatment.