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

• Published in: Science (American Association for the Advancement of Science) Vol. 296; no. 5567; pp. 530 - 534
• Main Authors: Tran, Hien, Brunet, Anne, Grenier, Jill M., Datta, Sandeep R., Fornace, Albert J., DiStefano, Peter S., Chiang, Lillian W., Greenberg, Michael E.
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for the Advancement of Science 19.04.2002; American Association for the Advancement of Science; The American Association for the Advancement of Science
• Subjects: Akt protein; Analysis; Animals; Antibodies; Biological and medical sciences; Cell cycle; Cell Line; Cell lines; Cell physiology; Chromones - pharmacology; Deoxyribonucleic acid; DNA; DNA binding proteins; DNA Damage; DNA Repair; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Fibroblasts; Forkhead Box Protein O1; Forkhead Box Protein O3; Forkhead Transcription Factors; FOXO3a protein; Fundamental and applied biological sciences. Psychology; G2 Phase; Gadd45 protein; GADD45 Proteins; Gene Expression Profiling; Gene Expression Regulation; Genes; Genes, Reporter; Humans; Interphase; Intracellular Signaling Peptides and Proteins; Mitosis; Molecular and cellular biology; Molecular genetics; Morpholines - pharmacology; Mutagenesis. Repair; Neurology; Promoter Regions, Genetic; Protein kinases; Proteins; Proteins - genetics; Proteins - metabolism; Rats; Recombinant Fusion Proteins - metabolism; Signal transduction; T tests; Tamoxifen - analogs & derivatives; Tamoxifen - pharmacology; Transcription Factors - genetics; Transcription Factors - metabolism; Transfection; Ultraviolet Rays; Signal transduction; Vertebrata; Cell line; Mammalia; Growth; Cell cycle; DNA chip; Gene expression; Transcription factor; DNA repair; Stress
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1068712

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 G2to 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.