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. Greenberg1
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.
To whom correspondence should be addressed. E-mail:
michael.greenberg{at}tch.harvard.edu
