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

George A. Garinis, Lieneke M. Uittenboogaard, Heike Stachelscheid, Maria Fousteri, Wilfred van Ijcken, Timo M. Breit, Harry van Steeg, Leon H.F. Mullenders, Gijsbertus T.J. van der Horst, Jens C. Brüning, Carien M. Niessen, Jan H.J. Hoeijmakers, Björn Schumacher

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

117 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)604-615
Aantal pagina's12
TijdschriftNature Cell Biology
Volume11
Nummer van het tijdschrift5
DOI's
StatusGepubliceerd - 2009
Extern gepubliceerdJa

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