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Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development

Author

Listed:
  • Yijie Gao

    (Howard Hughes Medical Institute, The Children's Hospital, and Centre for Blood Research
    Harvard Medical School)

  • David O. Ferguson

    (Howard Hughes Medical Institute, The Children's Hospital, and Centre for Blood Research
    Harvard Medical School
    Brigham and Women's Hospital)

  • Wei Xie

    (Howard Hughes Medical Institute, The Children's Hospital, and Centre for Blood Research
    Harvard Medical School)

  • John P. Manis

    (Howard Hughes Medical Institute, The Children's Hospital, and Centre for Blood Research
    Harvard Medical School)

  • JoAnn Sekiguchi

    (Howard Hughes Medical Institute, The Children's Hospital, and Centre for Blood Research
    Harvard Medical School)

  • Karen M. Frank

    (Howard Hughes Medical Institute, The Children's Hospital, and Centre for Blood Research
    Harvard Medical School)

  • Jayanta Chaudhuri

    (Howard Hughes Medical Institute, The Children's Hospital, and Centre for Blood Research
    Harvard Medical School)

  • James Horner

    (Medicine and Genetics, Harvard Medical School and Dana Farber Cancer Institute)

  • Ronald A. DePinho

    (Medicine and Genetics, Harvard Medical School and Dana Farber Cancer Institute)

  • Frederick W. Alt

    (Howard Hughes Medical Institute, The Children's Hospital, and Centre for Blood Research
    Harvard Medical School)

Abstract

XRCC4 is a non-homologous end-joining protein employed in DNA double strand break repair and in V(D)J recombination1,2. In mice, XRCC4-deficiency causes a pleiotropic phenotype, which includes embryonic lethality and massive neuronal apoptosis2. When DNA damage is not repaired, activation of the cell cycle checkpoint protein p53 can lead to apoptosis3. Here we show that p53-deficiency rescues several aspects of the XRCC4-deficient phenotype, including embryonic lethality, neuronal apoptosis, and impaired cellular proliferation. However, there was no significant rescue of impaired V(D)J recombination or lymphocyte development. Although p53-deficiency allowed postnatal survival of XRCC4-deficient mice, they routinely succumbed to pro-B-cell lymphomas which had chromosomal translocations linking amplified c-myc oncogene and IgH locus sequences. Moreover, even XRCC4-deficient embryonic fibroblasts exhibited marked genomic instability including chromosomal translocations. Our findings support a crucial role for the non-homologous end-joining pathway as a caretaker of the mammalian genome, a role required both for normal development and for suppression of tumours.

Suggested Citation

  • Yijie Gao & David O. Ferguson & Wei Xie & John P. Manis & JoAnn Sekiguchi & Karen M. Frank & Jayanta Chaudhuri & James Horner & Ronald A. DePinho & Frederick W. Alt, 2000. "Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development," Nature, Nature, vol. 404(6780), pages 897-900, April.
    • Handle: RePEc:nat:nature:v:404:y:2000:i:6780:d:10.1038_35009138
    DOI: 10.1038/35009138
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    Cited by:

    1. Ross J. Hill & Nazareno Bona & Job Smink & Hannah K. Webb & Alastair Crisp & Juan I. Garaycoechea & Gerry P. Crossan, 2024. "p53 regulates diverse tissue-specific outcomes to endogenous DNA damage in mice," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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