DOI: 10.1126/science.1068712. DNA Repair Pathway Stimulated by the Forkhead Transcription Factor FOXO3a Through the Gadd45 Protein

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

10.1126/science.1068712

Crossref journal-article

American Association for the Advancement of Science (AAAS)

Science (221)

Abstract

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 G 2 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 G 2 -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.

Bibliography

Tran, H., Brunet, A., Grenier, J. M., Datta, S. R., Fornace, A. J., DiStefano, P. S., Chiang, L. W., & Greenberg, M. E. (2002). DNA Repair Pathway Stimulated by the Forkhead Transcription Factor FOXO3a Through the Gadd45 Protein. Science, 296(5567), 530â534.

Authors 8

Hien Tran (first)
Anne Brunet (additional)
Jill M. Grenier (additional)
Sandeep R. Datta (additional)
Albert J. Fornace (additional)
Peter S. DiStefano (additional)
Lillian W. Chiang (additional)
Michael E. Greenberg (additional)

References 28 Referenced 675

10.1016/S0092-8674(00)80595-4
10.1038/19328
10.1038/35008115
10.1038/40194
10.1126/science.278.5341.1319
10.1073/pnas.90.19.8905
10.1038/20208
10.1096/fasebj.13.11.1385
10.1038/35041682
10.1038/35044005
Supplementary Web material is available on Science Online at www.sciencemag.org/cgi/content/full/296/5567/530/DC1.
10.1093/nar/23.10.1686
Western blot immunofluorescence experiments and luciferase assays were performed as described (1). The GADD45 α (H-165) antibody was purchased from Santa Cruz.
A. Brunet H. Tran M. E. Greenberg unpublished data.
Smith M. L., et al., Oncogene 13, 2255 (1996). / Oncogene by Smith M. L. (1996)
10.1073/pnas.051630598
Isolation of mRNA and transcriptional profiling experiments were performed as described previously in (16) and as decribed in (11).
Fornace A. J., et al., Mol. Cell. Biol. 9, 4196 (1989). / Mol. Cell. Biol. by Fornace A. J. (1989)
10.1016/S0092-8674(00)81619-0
Zhan Q., et al., Mol. Cell. Biol. 13, 4242 (1993). / Mol. Cell. Biol. by Zhan Q. (1993)
The plasmid encoding the GADD45A promoter driving the luciferase reporter gene and HA- GADD45A in a mammalian expression vector were kind gifts of D. Haber and were described previously (27).
10.1128/MCB.20.10.3705-3714.2000
10.1073/pnas.96.7.3706
10.1038/13802
10.1038/35099574
10.1016/0921-8734(89)90035-0
10.1016/S0092-8674(00)80769-2
We thank members of the Greenberg lab for their support. In particular we thank A. Nigh and W. Chen for help with the quantitative real-time PCR; A. West J. Zieg and R. Dolmetsch for their comments on the manuscript; B. Demple for helpful discussions and critical reading of manuscript; and A. Flint for his help in analyzing the FACS samples at the Howard Hughes FACS Facility. Supported by a Senior Scholars Award from the Ellison Foundation NIH grant PO1-HD24926 and Mental Retardation Research Center grant NIHP30-HD18655 (M.E.G.). A.B. was supported by a Goldenson Berenberg Fellowship. M.E.G. also acknowledges the generous contribution of the F. M. Kirby Foundation to the Division of Neuroscience.

Dates

Type	When
Created	23 years, 1 month ago (July 27, 2002, 1:54 a.m.)
Deposited	1 year, 7 months ago (Jan. 9, 2024, 5:38 p.m.)
Indexed	2 days, 12 hours ago (Aug. 26, 2025, 2:31 a.m.)
Issued	23 years, 4 months ago (April 19, 2002)
Published	23 years, 4 months ago (April 19, 2002)
Published Print	23 years, 4 months ago (April 19, 2002)

Funders 0

None

BibTeX

@article{Tran_2002, title={DNA Repair Pathway Stimulated by the Forkhead Transcription Factor FOXO3a Through the Gadd45 Protein}, volume={296}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.1068712}, DOI={10.1126/science.1068712}, number={5567}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Tran, Hien and Brunet, Anne and Grenier, Jill M. and Datta, Sandeep R. and Fornace, Albert J. and DiStefano, Peter S. and Chiang, Lillian W. and Greenberg, Michael E.}, year={2002}, month=apr, pages={530–534} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2025,
        8,
        26
      ]
    ],
    "date-time": "2025-08-26T06:31:34Z",
    "timestamp": 1756189894696
  },
  "reference-count": 28,
  "publisher": "American Association for the Advancement of Science (AAAS)",
  "issue": "5567",
  "content-domain": {
    "domain": [],
    "crossmark-restriction": false
  },
  "published-print": {
    "date-parts": [
      [
        2002,
        4,
        19
      ]
    ]
  },
  "abstract": "<jats:p>\n            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 G\n            <jats:sub>2</jats:sub>\n            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 G\n            <jats:sub>2</jats:sub>\n            -M checkpoint. The growth arrest and DNA damage response gene\n            <jats:italic>Gadd45a</jats:italic>\n            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.\n          </jats:p>",
  "DOI": "10.1126/science.1068712",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2002,
        7,
        27
      ]
    ],
    "date-time": "2002-07-27T05:54:32Z",
    "timestamp": 1027749272000
  },
  "page": "530-534",
  "source": "Crossref",
  "is-referenced-by-count": 675,
  "title": "DNA Repair Pathway Stimulated by the Forkhead Transcription Factor FOXO3a Through the Gadd45 Protein",
  "prefix": "10.1126",
  "volume": "296",
  "author": [
    {
      "given": "Hien",
      "family": "Tran",
      "sequence": "first",
      "affiliation": [
        {
          "name": "Division of Neuroscience, Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA."
        }
      ]
    },
    {
      "given": "Anne",
      "family": "Brunet",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Division of Neuroscience, Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA."
        }
      ]
    },
    {
      "given": "Jill M.",
      "family": "Grenier",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Millennium Pharmaceuticals, Inc., 640 Memorial Drive, Cambridge, MA 02139, USA."
        }
      ]
    },
    {
      "given": "Sandeep R.",
      "family": "Datta",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Division of Neuroscience, Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA."
        }
      ]
    },
    {
      "suffix": "Jr.",
      "given": "Albert J.",
      "family": "Fornace",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Building 37, Room 6144, NCI, National Institutes of Health, 37 Convent Drive MSC 4255, Bethesda, MD 20892, USA."
        }
      ]
    },
    {
      "given": "Peter S.",
      "family": "DiStefano",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Millennium Pharmaceuticals, Inc., 640 Memorial Drive, Cambridge, MA 02139, USA."
        }
      ]
    },
    {
      "given": "Lillian W.",
      "family": "Chiang",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Millennium Pharmaceuticals, Inc., 640 Memorial Drive, Cambridge, MA 02139, USA."
        }
      ]
    },
    {
      "given": "Michael E.",
      "family": "Greenberg",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Division of Neuroscience, Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA."
        }
      ]
    }
  ],
  "member": "221",
  "reference": [
    {
      "key": "e_1_3_1_2_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0092-8674(00)80595-4"
    },
    {
      "key": "e_1_3_1_3_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/19328"
    },
    {
      "key": "e_1_3_1_4_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/35008115"
    },
    {
      "key": "e_1_3_1_5_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/40194"
    },
    {
      "key": "e_1_3_1_6_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.278.5341.1319"
    },
    {
      "key": "e_1_3_1_7_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.90.19.8905"
    },
    {
      "key": "e_1_3_1_8_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/20208"
    },
    {
      "key": "e_1_3_1_9_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1096/fasebj.13.11.1385"
    },
    {
      "key": "e_1_3_1_10_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/35041682"
    },
    {
      "key": "e_1_3_1_11_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/35044005"
    },
    {
      "key": "e_1_3_1_12_2",
      "unstructured": "Supplementary Web material is available on Science Online at www.sciencemag.org/cgi/content/full/296/5567/530/DC1."
    },
    {
      "key": "e_1_3_1_13_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/nar/23.10.1686"
    },
    {
      "key": "e_1_3_1_14_2",
      "unstructured": "Western blot immunofluorescence experiments and luciferase assays were performed as described (1). The GADD45 \u03b1 (H-165) antibody was purchased from Santa Cruz."
    },
    {
      "key": "e_1_3_1_15_2",
      "unstructured": "A. Brunet H. Tran M. E. Greenberg unpublished data."
    },
    {
      "key": "e_1_3_1_16_2",
      "first-page": "2255",
      "volume": "13",
      "author": "Smith M. L.",
      "year": "1996",
      "unstructured": "Smith M. L., et al., Oncogene 13, 2255 (1996).",
      "journal-title": "Oncogene"
    },
    {
      "key": "e_1_3_1_17_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.051630598"
    },
    {
      "key": "e_1_3_1_18_2",
      "unstructured": "Isolation of mRNA and transcriptional profiling experiments were performed as described previously in (16) and as decribed in (11)."
    },
    {
      "key": "e_1_3_1_19_2",
      "first-page": "4196",
      "volume": "9",
      "author": "Fornace A. J.",
      "year": "1989",
      "unstructured": "Fornace A. J., et al., Mol. Cell. Biol. 9, 4196 (1989).",
      "journal-title": "Mol. Cell. Biol."
    },
    {
      "key": "e_1_3_1_20_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0092-8674(00)81619-0"
    },
    {
      "key": "e_1_3_1_21_2",
      "first-page": "4242",
      "volume": "13",
      "author": "Zhan Q.",
      "year": "1993",
      "unstructured": "Zhan Q., et al., Mol. Cell. Biol. 13, 4242 (1993).",
      "journal-title": "Mol. Cell. Biol."
    },
    {
      "key": "e_1_3_1_22_2",
      "unstructured": "The plasmid encoding the GADD45A promoter driving the luciferase reporter gene and HA- GADD45A in a mammalian expression vector were kind gifts of D. Haber and were described previously (27)."
    },
    {
      "key": "e_1_3_1_23_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1128/MCB.20.10.3705-3714.2000"
    },
    {
      "key": "e_1_3_1_24_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.96.7.3706"
    },
    {
      "key": "e_1_3_1_25_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/13802"
    },
    {
      "key": "e_1_3_1_26_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/35099574"
    },
    {
      "key": "e_1_3_1_27_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0921-8734(89)90035-0"
    },
    {
      "key": "e_1_3_1_28_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0092-8674(00)80769-2"
    },
    {
      "key": "e_1_3_1_29_2",
      "unstructured": "We thank members of the Greenberg lab for their support. In particular we thank A. Nigh and W. Chen for help with the quantitative real-time PCR; A. West J. Zieg and R. Dolmetsch for their comments on the manuscript; B. Demple for helpful discussions and critical reading of manuscript; and A. Flint for his help in analyzing the FACS samples at the Howard Hughes FACS Facility. Supported by a Senior Scholars Award from the Ellison Foundation NIH grant PO1-HD24926 and Mental Retardation Research Center grant NIHP30-HD18655 (M.E.G.). A.B. was supported by a Goldenson Berenberg Fellowship. M.E.G. also acknowledges the generous contribution of the F. M. Kirby Foundation to the Division of Neuroscience."
    }
  ],
  "container-title": "Science",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://www.science.org/doi/pdf/10.1126/science.1068712",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2024,
        1,
        9
      ]
    ],
    "date-time": "2024-01-09T22:38:07Z",
    "timestamp": 1704839887000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://www.science.org/doi/10.1126/science.1068712"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        2002,
        4,
        19
      ]
    ]
  },
  "references-count": 28,
  "journal-issue": {
    "issue": "5567",
    "published-print": {
      "date-parts": [
        [
          2002,
          4,
          19
        ]
      ]
    }
  },
  "alternative-id": [
    "10.1126/science.1068712"
  ],
  "URL": "http://dx.doi.org/10.1126/science.1068712",
  "relation": {},
  "ISSN": [
    "0036-8075",
    "1095-9203"
  ],
  "subject": [],
  "container-title-short": "Science",
  "published": {
    "date-parts": [
      [
        2002,
        4,
        19
      ]
    ]
  }
}