DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein.
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.
Tran
Hien
H
Division of Neuroscience, Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Brunet
Anne
A
Grenier
Jill M
JM
Datta
Sandeep R
SR
Fornace
Albert J
AJ
DiStefano
Peter S
PS
Chiang
Lillian W
LW
Greenberg
Michael E
ME
D000818:Animals; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D016195:G2 Phase; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008938:Mitosis; D009025:Morpholines / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014466:Ultraviolet Rays; D000097642:GADD45 Proteins
D002867:Chromones; D004268:DNA-Binding Proteins; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D011506:Proteins; D011993:Recombinant Fusion Proteins; D013629:Tamoxifen; D014157:Transcription Factors; D000097642:GADD45 Proteins; C085126:FOXO1 protein, human; C499515:FOXO3 protein, rat; C016601:afimoxifene; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one