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

G Garinis, Lieneke Uittenboogaard, H Stachelscheid, M Fousteri, Wilfred van Ijcken, TM (Timo) Breit, H van Steeg, LHF Mullenders, Bert van der Horst, JC Bruning, CM Niessen, Jan Hoeijmakers, Bjorn Schumacher

Research output: Contribution to journalArticleAcademicpeer-review

108 Citations (Scopus)

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.
Original languageUndefined/Unknown
Pages (from-to)604-U370
JournalNature Cell Biology
Volume11
Issue number5
DOIs
Publication statusPublished - 2009

Cite this