Persistent Transcription-blocking DNA Lesions Trigger Somatic Growth Attenuation Associated with Longevity

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2009 Apr 14

PMID 19363488

Citations 78

Authors

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 Bruning

Carien M Niessen

Jan H J Hoeijmakers

Bjorn Schumacher

Affiliations

Soon will be listed here.

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.

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