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

Nature Cell Biology volume 11, pages 604–615 (2009)Cite this article

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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Figure 1: Shared biological processes after induction of DNA damage in vitro and ageing in vivo.
Figure 2: IGF-1R and GHR are repressed in response to persistent DNA damage, leading to IGF-1 resistance.
Figure 3: Response to UV irradiation induces resistance to oxidative stress.
Figure 4: UV irradiation leads to IGF-1R and GHR attenuation in quiescent and terminally differentiated cells.
Figure 5: Prolonged IGF-1R and GHR repression in cells from NER-deficient progeroid mice.
Figure 6: Attenuation of IGF-1R and GHR expression in response to illudin S but not to oxidative damage and ionizing irradiation.
Figure 7: Repair of persistent CPD lesions alleviates IGF-1R and GHR repression and resistance to oxidative stress.
Figure 8: Stochastic DNA damage resulting from extrinsic and intrinsic sources contributes to cancer and ageing.

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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).

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Authors and Affiliations

  1. MGC Department of Cell Biology and Genetics, Center for Biomedical Genetics, Erasmus Medical Center, PO Box 1738, Rotterdam, 3000 DR, 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, Heraklion, GR70013, Greece

    George A. Garinis

  3. Center for Molecular Medicine Cologne, University of Cologne, Cologne, 50931, Germany

    Heike Stachelscheid & Carien M. Niessen

  4. Institute for Genetics, University of Cologne, Cologne, 50674, Germany

    Heike Stachelscheid & Jens C. Brüning

  5. Department of Toxicogenetics, LUMC, Leiden, 2300RC, The Netherlands

    Maria Fousteri & Leon H. F. Mullenders

  6. Erasmus Center for Biomics, Erasmus Medical Center, Rotterdam, 3000DR, The Netherlands

    Wilfred van Ijcken

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

    Timo M. Breit

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

    Harry van Steeg

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

    Jens C. Brüning, Carien M. Niessen & Björn Schumacher

  10. Department of Dermatology, University of Cologne, Cologne, 50931, 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.

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Correspondence to Björn Schumacher.

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

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Garinis, G., Uittenboogaard, L., Stachelscheid, H. et al. Persistent transcription-blocking DNA lesions trigger somatic growth attenuation associated with longevity. Nat Cell Biol 11, 604–615 (2009). https://doi.org/10.1038/ncb1866

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