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Science 19 April 2002:
Vol. 296. no. 5567, pp. 530 - 534
DOI: 10.1126/science.1068712
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Reports

DNA Repair Pathway Stimulated by the Forkhead Transcription Factor FOXO3a Through the Gadd45 Protein

Hien Tran,1* Anne Brunet,1* Jill M. Grenier,2 Sandeep R. Datta,1 Albert J. Fornace Jr.,3 Peter S. DiStefano,2 Lillian W. Chiang,2 Michael E. Greenberg1dagger

The signaling pathway from phosphoinositide 3-kinase to the protein kinase Akt controls organismal life-span in invertebrates and cell survival and proliferation in mammals by inhibiting the activity of members of the FOXO family of transcription factors. We show that mammalian FOXO3a also functions at the G2 to M checkpoint in the cell cycle and triggers the repair of damaged DNA. By gene array analysis, FOXO3a was found to modulate the expression of several genes that regulate the cellular response to stress at the G2-M checkpoint. The growth arrest and DNA damage response gene Gadd45a appeared to be a direct target of FOXO3a that mediates part of FOXO3a's effects on DNA repair. These findings indicate that in mammals FOXO3a regulates the resistance of cells to stress by inducing DNA repair and thereby may also affect organismal life-span.

1 Division of Neuroscience, Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
2 Millennium Pharmaceuticals, Inc., 640 Memorial Drive, Cambridge, MA 02139, USA.
3 Building 37, Room 6144, NCI, National Institutes of Health, 37 Convent Drive MSC 4255, Bethesda, MD 20892, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: michael.greenberg{at}tch.harvard.edu

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