A conserved long-distance telomeric silencing mechanism suppresses mTOR signaling in aging human fibroblasts-Reference-Cited by-同舟云学术

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

Published:2022-08-19 Issue:33 Volume:8 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Jäger Kathrin¹²^ORCID,Mensch Juliane¹²^ORCID,Grimmig Maria Elisabeth¹^ORCID,Neuner Bruno³,Gorzelniak Kerstin⁴,Türkmen Seval⁵⁶^ORCID,Demuth Ilja⁷⁸^ORCID,Hartmann Alexander¹^ORCID,Hartmann Christiane⁹^ORCID,Wittig Felix¹⁰^ORCID,Sporbert Anje¹¹,Hermann Andreas⁹¹²¹³^ORCID,Fuellen Georg¹⁴^ORCID,Möller Steffen¹⁴^ORCID,Walter Michael¹²^ORCID

Affiliation:

1. Institute of Clinical Chemistry and Laboratory Medicine, Rostock University Medical Center, University of Rostock, Rostock, Germany.

2. Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Berlin, Germany.

3. Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Anesthesiology and Intensive Care Medicine, Berlin, Germany.

4. Unfallkrankenhaus Berlin, Institute of Laboratory Medicine, Berlin, Germany.

5. LNS Hematooncogenetics, National Center of Genetics Luxembourg, Dudelange, Luxemburg.

6. Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Medical Genetics and Human Genetics, Berlin, Germany.

7. Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Endocrinology and Metabolism, Berlin, Germany.

8. Berlin Institute of Health at Charité–Universitätsmedizin Berlin, BCRT - Berlin Institute of Health Center for Regenerative Therapies, Berlin, Germany.

9. Translational Neurodegeneration Section “Albrecht-Kossel”, Department of Neurology, Rostock University Medical Center, University of Rostock, 18147 Rostock, Germany.

10. Institute of Pharmacology and Toxicology, Rostock University Medical Center, University of Rostock, Rostock, Germany.

11. Advanced Light Microscopy, Max Delbrück Center for Molecular Medicine, Berlin, Germany.

12. Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) Rostock/Greifswald, Rostock, Germany.

13. Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Center Rostock, Rostock, Germany.

14. Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock, Germany.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Reference79 articles.

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3. Role of Telomeres and Telomerase in Aging and Cancer

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