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A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis

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  • Laura J. Niedernhofer

    (Center for Biomedical Genetics Medical Genetic Center Department of Cell Biology and Genetics
    University of Pittsburgh School of Medicine)

  • George A. Garinis

    (Center for Biomedical Genetics Medical Genetic Center Department of Cell Biology and Genetics)

  • Anja Raams

    (Center for Biomedical Genetics Medical Genetic Center Department of Cell Biology and Genetics)

  • Astrid S. Lalai

    (Center for Biomedical Genetics Medical Genetic Center Department of Cell Biology and Genetics)

  • Andria Rasile Robinson

    (University of Pittsburgh School of Medicine)

  • Esther Appeldoorn

    (Center for Biomedical Genetics Medical Genetic Center Department of Cell Biology and Genetics)

  • Hanny Odijk

    (Center for Biomedical Genetics Medical Genetic Center Department of Cell Biology and Genetics)

  • Roos Oostendorp

    (Center for Biomedical Genetics Medical Genetic Center Department of Cell Biology and Genetics)

  • Anwaar Ahmad

    (University of Pittsburgh School of Medicine)

  • Wibeke van Leeuwen

    (Department of Experimental Radiology)

  • Arjan F. Theil

    (Center for Biomedical Genetics Medical Genetic Center Department of Cell Biology and Genetics)

  • Wim Vermeulen

    (Center for Biomedical Genetics Medical Genetic Center Department of Cell Biology and Genetics)

  • Gijsbertus T. J. van der Horst

    (Center for Biomedical Genetics Medical Genetic Center Department of Cell Biology and Genetics)

  • Peter Meinecke

    (Abteilung für Medizinische Genetik, Altonaer KinderKrankenhaus)

  • Wim J. Kleijer

    (Erasmus Medical Center)

  • Jan Vijg

    (The Buck Institute for Age Research)

  • Nicolaas G. J. Jaspers

    (Center for Biomedical Genetics Medical Genetic Center Department of Cell Biology and Genetics)

  • Jan H. J. Hoeijmakers

    (Center for Biomedical Genetics Medical Genetic Center Department of Cell Biology and Genetics)

Abstract

XPF–ERCC1 endonuclease is required for repair of helix-distorting DNA lesions and cytotoxic DNA interstrand crosslinks. Mild mutations in XPF cause the cancer-prone syndrome xeroderma pigmentosum. A patient presented with a severe XPF mutation leading to profound crosslink sensitivity and dramatic progeroid symptoms. It is not known how unrepaired DNA damage accelerates ageing or its relevance to natural ageing. Here we show a highly significant correlation between the liver transcriptome of old mice and a mouse model of this progeroid syndrome. Expression data from XPF–ERCC1-deficient mice indicate increased cell death and anti-oxidant defences, a shift towards anabolism and reduced growth hormone/insulin-like growth factor 1 (IGF1) signalling, a known regulator of lifespan. Similar changes are seen in wild-type mice in response to chronic genotoxic stress, caloric restriction, or with ageing. We conclude that unrepaired cytotoxic DNA damage induces a highly conserved metabolic response mediated by the IGF1/insulin pathway, which re-allocates resources from growth to somatic preservation and life extension. This highlights a causal contribution of DNA damage to ageing and demonstrates that ageing and end-of-life fitness are determined both by stochastic damage, which is the cause of functional decline, and genetics, which determines the rates of damage accumulation and decline.

Suggested Citation

  • Laura J. Niedernhofer & George A. Garinis & Anja Raams & Astrid S. Lalai & Andria Rasile Robinson & Esther Appeldoorn & Hanny Odijk & Roos Oostendorp & Anwaar Ahmad & Wibeke van Leeuwen & Arjan F. The, 2006. "A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis," Nature, Nature, vol. 444(7122), pages 1038-1043, December.
  • Handle: RePEc:nat:nature:v:444:y:2006:i:7122:d:10.1038_nature05456
    DOI: 10.1038/nature05456
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    Citations

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    Cited by:

    1. Chia-Yu Guh & Hong-Jhih Shen & Liv WeiChien Chen & Pei-Chen Chiu & I-Hsin Liao & Chen-Chia Lo & Yunfei Chen & Yu-Hung Hsieh & Ting-Chia Chang & Chien-Ping Yen & Yi-Yun Chen & Tom Wei-Wu Chen & Liuh-Yo, 2022. "XPF activates break-induced telomere synthesis," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    2. Alba Muniesa-Vargas & Carlota Davó-Martínez & Cristina Ribeiro-Silva & Melanie van der Woude & Karen L. Thijssen & Ben Haspels & David Häckes & Ülkem U. Kaynak & Roland Kanaar & Jurgen A. Marteijn & A, 2024. "Persistent TFIIH binding to non-excised DNA damage causes cell and developmental failure," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. 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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