Letter abstract
Nature Cell Biology 10, 460 - 467 (2008)
Published online: 16 March 2008 | Corrected online: 1 October 2009 | doi:10.1038/ncb1709
There is a Corrigendum (November 2009) associated with this Letter.
Functional interaction between FOXO3a and ATM regulates DNA damage response
Wen-Bin Tsai1, Young Min Chung1, Yoko Takahashi1, Zhaohui Xu1 & Mickey C.-T. Hu1,2
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 ataxia-telangiectasia mutated (ATM) and its downstream mediators to control damage-induced cell-cycle checkpoints and DNA repair1, 2, 3. Here, we show that FOXO3a interacts with ATM to promote phosphorylation of ATM at Ser 1981 and prompting 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 signalling, the intra-S-phase or G2–M cell-cycle checkpoints, and the repair of damaged DNA, whereas cells lacking FOXO3a did not trigger the DNA-repair mechanism after DNA damage. 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 the DNA-damage response.
- Departments of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
- Graduate School of Biomedical Sciences, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Correspondence to: Mickey C.-T. Hu1,2 e-mail: michu@mdanderson.org
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