{Delta}Np73{beta} puts the brakes on DNA repair

Abstract

Mammalian cells are barraged with endogenous metabolic byproducts and environmental insults that can lead to nearly a million genomic lesions per cell per day. Networks of proteins that repair these lesions are essential for genome maintenance, and a compromise in these pathways propagates mutations that can cause aging and cancer. The p53 tumor suppressor plays a central role in repairing the effects of DNA damage, and has therefore earned the title of "guardian of the genome." In this issue of Genes & Development, Wilhelm and colleagues (pp. 549-560) demonstrate that p73-an older sibling of p53-inhibits pathways that resolve DNA double-strand breaks.

Figure 1.

Model for the role of ΔNp73β in the DDR. The data presented by Wilhelm et al. (2010) support a model in which ΔNp73β inhibits ATM–p53 signaling. (Left) In normal cells, ΔNp73β interacts with 53BP1, and p53 activity is kept in check via MDM2-mediated degradation. (Right) In response to dsDNA breaks triggered by DNA damage, the ΔNp73β:53BP1 complex is recruited to sites of DNA damage, ATM is activated, and MDM2’s inhibitory effect on p53 is alleviated; in the absence of ΔNp73, this pathway is enhanced. Although p73 is localized to DNA damage-induced foci under physiological conditions, this association is clearly not needed for 53BP1 localization, as 53BP1 localizes to sites of DNA damage even in the absence of ΔNp73.