Functional interaction between FOXO3a and ATM regulates DNA damage response
Open Access
- 16 March 2008
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 10 (4), 460-467
- https://doi.org/10.1038/ncb1709
Abstract
The maintenance of genomic stability in cells is relentlessly challenged by environmental stresses that induce DNA breaks, which activate the DNA-damage pathway mediated by protein complexes such as ataxia-telangiectasia mutated (ATM) and its downstream mediators to sense DNA damage and control damage-induced cell-cycle checkpoints and DNA repair1–3. Here we show that FOXO3a interacts with ATM to promote phosphorylation of ATM at Serine-1981 (ATM-pS1981) and to prompt its downstream mediators to form nuclear foci in response to DNA damage. Silencing FOXO3a in cells abrogates the formation of ATM-pS1981 and phospho-histone H2AX foci after DNA damage. Increasing FOXO3a in cells promotes ATM-regulated signaling, intra-S-phase or G2/M cell-cycle checkpoint, and repair of damaged DNA, whereas cells lacking FOXO3a could not trigger the DNA-repair mechanism after DNA damage. Interestingly, the carboxy-terminal domain of FOXO3a binds to the FAT domain of ATM, thereby contributing to the activation of ATM. These results suggest that ATM may be regulated directly by FOXO3a in DNA damage response.This publication has 29 references indexed in Scilit:
- Molecular Linkage Between the Kinase ATM and NF-κB Signaling in Response to Genotoxic StimuliScience, 2006
- DNA damage response as a candidate anti-cancer barrier in early human tumorigenesisNature, 2005
- Cell-cycle checkpoints and cancerNature, 2004
- IκB Kinase Promotes Tumorigenesis through Inhibition of Forkhead FOXO3aCell, 2004
- A DNA damage checkpoint response in telomere-initiated senescenceNature, 2003
- ATM and related protein kinases: safeguarding genome integrityNature Reviews Cancer, 2003
- DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociationNature, 2003
- Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stressNature, 2002
- FOXO Forkhead Transcription Factors Induce G2-M Checkpoint in Response to Oxidative StressPublished by Elsevier BV ,2002
- Genomic Instability in Mice Lacking Histone H2AXScience, 2002