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Persistent transcription-blocking DNA lesions trigger somatic growth attenuation associated with longevity

Nature Cell Biology volume 11, pages 604615 (2009) | Download Citation

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Abstract

The accumulation of stochastic DNA damage throughout an organism's lifespan is thought to contribute to ageing. Conversely, ageing seems to be phenotypically reproducible and regulated through genetic pathways such as the insulin-like growth factor-1 (IGF-1) and growth hormone (GH) receptors, which are central mediators of the somatic growth axis. Here we report that persistent DNA damage in primary cells from mice elicits changes in global gene expression similar to those occurring in various organs of naturally aged animals. We show that, as in ageing animals, the expression of IGF-1 receptor and GH receptor is attenuated, resulting in cellular resistance to IGF-1. This cell-autonomous attenuation is specifically induced by persistent lesions leading to stalling of RNA polymerase II in proliferating, quiescent and terminally differentiated cells; it is exacerbated and prolonged in cells from progeroid mice and confers resistance to oxidative stress. Our findings suggest that the accumulation of DNA damage in transcribed genes in most if not all tissues contributes to the ageing-associated shift from growth to somatic maintenance that triggers stress resistance and is thought to promote longevity.

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Acknowledgements

We thank Christel Kockx, Zeliha Ozgur and Anja Raams for technical assistance, Casper Hoogenraad for neuron cultures, and Anton Gartner and Francis Barr for comments on the manuscript. This research was supported by the Netherlands Organization for Scientific Research (NWO) and the Netherlands Genomics Initiative (NGI; NGI/NWO 05040202), SenterNovem IOP-Genomics (IGE03009), the NIH (1PO1 AG17242), the National Institute of Environmental Health Sciences (NIEHS; 1UO1 ES011044), the EC (QRTL-1999-02002) and the Dutch Cancer Society (EUR 99-2004). G.G. acknowledges support from the Cancer Genomics Centre and B.S. from EMBO long-term, Marie Curie Intra-European fellowships,Veni grant of the NWO and the Deutsche Forschungsgemeinschaft (CECAD and SFB829).

Author information

Affiliations

  1. MGC Department of Cell Biology and Genetics, Center for Biomedical Genetics, Erasmus Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands.

    • George A. Garinis
    • , Lieneke M. Uittenboogaard
    • , Gijsbertus T. J. van der Horst
    • , Jan H. J. Hoeijmakers
    •  & Björn Schumacher
  2. Institute of Molecular Biology and Biotechnology, FORTH, GR70013 Heraklion, Greece.

    • George A. Garinis
  3. Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.

    • Heike Stachelscheid
    •  & Carien M. Niessen
  4. Institute for Genetics, University of Cologne, 50674 Cologne, Germany.

    • Heike Stachelscheid
    •  & Jens C. Brüning
  5. Department of Toxicogenetics, LUMC, 2300RC Leiden, The Netherlands.

    • Maria Fousteri
    •  & Leon H. F. Mullenders
  6. Erasmus Center for Biomics, Erasmus Medical Center, 3000DR Rotterdam, The Netherlands.

    • Wilfred van Ijcken
  7. Integrative Bioinformatics Unit, Institute for Informatics, Faculty of Science, University of Amsterdam, 1098SM Amsterdam, The Netherlands.

    • Timo M. Breit
  8. National Institute of Public Health and the Environment (RIVM), Laboratory of Toxicology, Pathology and Genetics (TOX), 3720BA Bilthoven, The Netherlands.

    • Harry van Steeg
  9. Cologne Excellence Cluster for Cellular Stress Responses in Aging Associated Diseases (CECAD), 50674 Cologne, Germany.

    • Jens C. Brüning
    • , Carien M. Niessen
    •  & Björn Schumacher
  10. Department of Dermatology, University of Cologne, 50931 Cologne, Germany.

    • Carien M. Niessen

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Contributions

Conceived and designed the experiments: BS. Performed the experiments and analysed the data: BS, GAG, LMU, HS, MF. Contributed reagents/materials/analysis tools: WvI, TMB, HvS, LHFM, GvdH, JCB, CMN. Wrote the paper: BS, JHJH, GAG.

Competing interests

J.H.J.H. is the Chief Scientific Officer of DNage/Pharming.

Corresponding author

Correspondence to Björn Schumacher.

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DOI

https://doi.org/10.1038/ncb1866

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