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

• Published in: Nature cell biology Vol. 11; no. 5; pp. 604 - 615
• Main Authors: Garinis, George A., Uittenboogaard, Lieneke M., Stachelscheid, Heike, Fousteri, Maria, van Ijcken, Wilfred, Breit, Timo M., van Steeg, Harry, Mullenders, Leon H. F., van der Horst, Gijsbertus T. J., Brüning, Jens C., Niessen, Carien M., Hoeijmakers, Jan H. J., Schumacher, Björn
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2009; Nature Publishing Group
• Subjects: Accumulation; Aging; Aging - physiology; Animal Structures - metabolism; Animals; Biology; Biomedical and Life Sciences; Cancer; Cancer Research; Causes of; Cell Biology; Deoxyribonucleic acid; Developmental Biology; DNA; DNA - radiation effects; DNA damage; DNA Damage - physiology; DNA Repair - physiology; Gene expression; Gene Expression Profiling; Genetic aspects; Genetics; Genomes; Growth - physiology; Growth - radiation effects; Growth factors; Health aspects; Humans; Insulin-like growth factors; Lesions; Life Sciences; Life span; Longevity; Longevity - physiology; Longevity - radiation effects; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Mutation; Neoplasms - etiology; Neoplasms - genetics; Oxidative stress; Oxidative Stress - physiology; Progeria - genetics; Progeria - metabolism; Rats; Receptor, IGF Type 1 - genetics; Receptor, IGF Type 1 - metabolism; Receptors, Somatotropin - genetics; Receptors, Somatotropin - metabolism; RNA polymerase; RNA Polymerase II - metabolism; Stem Cells; Stress, Physiological - physiology; Transcription, Genetic - genetics; Transcription, Genetic - radiation effects; Ultraviolet Rays; Netherlands; Germany
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb1866

The 'somatic growth axis' involving IGF-1 and growth hormone is implicated in longevity. Persistent transcription-blocking DNA damage attenuates growth hormone and IGF-1 receptor expression and precipitates other ageing associated transcriptional changes, as well as inhibiting somatic growth. 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.