Persistent transcription-blocking DNA lesions trigger somatic growth attenuation associated with longevity.
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, Rotterdam 3000 DR, The Netherlands.
George A
GA
Garinis
Lieneke M
LM
Uittenboogaard
Heike
H
Stachelscheid
Maria
M
Fousteri
Wilfred
W
van Ijcken
Timo M
TM
Breit
Harry
H
van Steeg
Leon H F
LH
Mullenders
Gijsbertus T J
GT
van der Horst
Jens C
JC
Brüning
Carien M
CM
Niessen
Jan H J
JH
Hoeijmakers
Björn
B
Schumacher
D000375:Aging / Q000502:physiology; D000825:Animal Structures / Q000378:metabolism; D000818:Animals; D004247:DNA / Q000528:radiation effects; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology; D020869:Gene Expression Profiling; D006128:Growth / Q000502:physiology* / Q000528:radiation effects; D006801:Humans; D008136:Longevity / Q000502:physiology* / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009369:Neoplasms / Q000209:etiology / Q000235:genetics; D018384:Oxidative Stress / Q000502:physiology; D011371:Progeria / Q000235:genetics / Q000378:metabolism; D012319:RNA Polymerase II / Q000378:metabolism; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000502:physiology; D014158:Transcription, Genetic / Q000235:genetics* / Q000528:radiation effects; D014466:Ultraviolet Rays
D011986:Receptors, Somatotropin; D004247:DNA; D017526:Receptor, IGF Type 1; D012319:RNA Polymerase II