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| Item Type: | Article |
|---|---|
| Title: | A conserved long-distance telomeric silencing mechanism suppresses mTOR signaling in aging human fibroblasts |
| Creators: |
Jäger, K.  ORCID: https://orcid.org/0000-0002-7535-5397, Mensch, J. ORCID: https://orcid.org/0000-0002-3021-0506, Grimmig, M.E. ORCID: https://orcid.org/0000-0002-9869-2353, Neuner, B., Gorzelniak, K., Türkmen, S. ORCID: https://orcid.org/0000-0002-4016-4777, Demuth, I. ORCID: https://orcid.org/0000-0002-4340-2523, Hartmann, A. ORCID: https://orcid.org/0000-0002-7314-8159, Hartmann, C. ORCID: https://orcid.org/0000-0001-8699-0794, Wittig, F. ORCID: https://orcid.org/0000-0003-3276-0891, Sporbert, A. ORCID: https://orcid.org/0000-0002-3738-1295, Hermann, A. ORCID: https://orcid.org/0000-0002-7364-7791, Fuellen, G. ORCID: https://orcid.org/0000-0002-4994-9829, Möller, S. ORCID: https://orcid.org/0000-0002-7187-4683 and Walter, M. ORCID: https://orcid.org/0000-0003-4758-9716
|
| 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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