FOXO3 signalling links ATM to the p53 apoptotic pathway following DNA damage
Open Access
- 1 January 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 3 (1), 1-13
- https://doi.org/10.1038/ncomms2008
Abstract
DNA damage as a result of environmental stress is recognized by sensor proteins that trigger repair mechanisms, or, if repair is unsuccessful, initiate apoptosis. Defects in DNA damage-induced apoptosis promote genomic instability and tumourigenesis. The protein ataxia-telangiectasia mutated (ATM) is activated by DNA double-strand breaks and regulates apoptosis via p53. Here we show that FOXO3 interacts with the ATM–Chk2–p53 complex, augments phosphorylation of the complex and induces the formation of nuclear foci in cells on DNA damage. FOXO3 is essential for DNA damage-induced apoptosis and conversely FOXO3 requires ATM, Chk2 and phosphorylated p53 isoforms to trigger apoptosis as a result of DNA damage. Under these conditions FOXO3 may also have a role in regulating chromatin retention of phosphorylated p53. These results suggest an essential link between FOXO3 and the ATM–Chk2–p53-mediated apoptotic programme following DNA damage.Keywords
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