A conserved long-distance telomeric silencing mechanism suppresses mTOR signaling in aging human fibroblasts
Authors
- K. Jäger
- J. Mensch
- M.E. Grimmig
- B. Neuner
- K. Gorzelniak
- S. Türkmen
- I. Demuth
- A. Hartmann
- C. Hartmann
- F. Wittig
- A. Sporbert
- A. Hermann
- G. Fuellen
- S. Möller
- M. Walter
Journal
- Science Advances
Citation
- Sci Adv 8 (33): eabk2814
Abstract
Telomeres are repetitive nucleotide sequences at the ends of each chromosome. It has been hypothesized that telomere attrition evolved as a tumor suppressor mechanism in large long-lived species. Long telomeres can silence genes millions of bases away through a looping mechanism called telomere position effect over long distances (TPE-OLD). The function of this silencing mechanism is unknown. We determined a set of 2322 genes with high positional conservation across replicatively aging species that includes known and candidate TPE-OLD genes that may mitigate potentially harmful effects of replicative aging. Notably, we identified PPP2R2C as a tumor suppressor gene, whose up-regulation by TPE-OLD in aged human fibroblasts leads to dephosphorylation of p70S6 kinase and mammalian target of rapamycin suppression. A mechanistic link between telomeres and a tumor suppressor mechanism supports the hypothesis that replicative aging fulfills a tumor suppressor function and motivates previously unknown antitumor and antiaging strategies.