Article abstract
Nature Cell Biology 11, 604 - 615 (2009)
Published online: 12 April 2009 | doi:10.1038/ncb1866
Persistent transcription-blocking DNA lesions trigger somatic growth attenuation associated with longevity
George A. Garinis1,2, Lieneke M. Uittenboogaard1, Heike Stachelscheid3,4, Maria Fousteri5, Wilfred van Ijcken6, Timo M. Breit7, Harry van Steeg8, Leon H. F. Mullenders5, Gijsbertus T. J. van der Horst1, Jens C. Brüning4,9, Carien M. Niessen3,9,10, Jan H. J. Hoeijmakers1 & Björn Schumacher1,9
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.
- MGC Department of Cell Biology and Genetics, Center for Biomedical Genetics, Erasmus Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands.
- Institute of Molecular Biology and Biotechnology, FORTH, GR70013 Heraklion, Greece.
- Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
- Institute for Genetics, University of Cologne, 50674 Cologne, Germany.
- Department of Toxicogenetics, LUMC, 2300RC Leiden, The Netherlands.
- Erasmus Center for Biomics, Erasmus Medical Center, 3000DR Rotterdam, The Netherlands.
- Integrative Bioinformatics Unit, Institute for Informatics, Faculty of Science, University of Amsterdam, 1098SM Amsterdam, The Netherlands.
- National Institute of Public Health and the Environment (RIVM), Laboratory of Toxicology, Pathology and Genetics (TOX), 3720BA Bilthoven, The Netherlands.
- Cologne Excellence Cluster for Cellular Stress Responses in Aging Associated Diseases (CECAD), 50674 Cologne, Germany.
- Department of Dermatology, University of Cologne, 50931 Cologne, Germany.
Correspondence to: Björn Schumacher1,9 e-mail: bjoern.schumacher@uni-koeln.de
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