A conserved long-distance telomeric silencing mechanism suppresses mTOR signaling in aging human fibroblasts

Jäger, K.; Mensch, J.; Grimmig, M.E.; Neuner, B.; Gorzelniak, K.; Türkmen, S.; Demuth, I.; Hartmann, A.; Hartmann, C.; Wittig, F.; Sporbert, A.; Hermann, A.; Fuellen, G.; Möller, S.; Walter, M.

A conserved long-distance telomeric silencing mechanism suppresses mTOR signaling in aging human fibroblasts

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Item Type:	Article
Title:	A conserved long-distance telomeric silencing mechanism suppresses mTOR signaling in aging human fibroblasts
Creators Name:	Jäger, K., Mensch, J., Grimmig, M.E., Neuner, B., Gorzelniak, K., Türkmen, S., Demuth, I., Hartmann, A., Hartmann, C., Wittig, F., Sporbert, A., Hermann, A., Fuellen, G., Möller, S. and Walter, M.
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.
Keywords:	Aging, Fibroblasts, Gene Silencing, TOR Serine-Threonine Kinases, Telomere
Source:	Science Advances
ISSN:	2375-2548
Publisher:	American Association for the Advancement of Science
Volume:	8
Number:	33
Page Range:	eabk2814
Date:	August 2022
Official Publication:	https://doi.org/10.1126/sciadv.abk2814
PubMed:	View item in PubMed

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