TY - JOUR
T1 - Persistent transcription-blocking DNA lesions trigger somatic growth attenuation associated with longevity
AU - Garinis, George A.
AU - Uittenboogaard, Lieneke M.
AU - Stachelscheid, Heike
AU - Fousteri, Maria
AU - van Ijcken, Wilfred
AU - Breit, Timo M.
AU - van Steeg, Harry
AU - Mullenders, Leon H.F.
AU - van der Horst, Gijsbertus T.J.
AU - Brüning, Jens C.
AU - Niessen, Carien M.
AU - Hoeijmakers, Jan H.J.
AU - Schumacher, Björn
N1 - Funding Information:
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).
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/67349287384
U2 - 10.1038/ncb1866
DO - 10.1038/ncb1866
M3 - Article
C2 - 19363488
AN - SCOPUS:67349287384
SN - 1465-7392
VL - 11
SP - 604
EP - 615
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 5
ER -