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

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.

Proposing candidate genes under telomeric control based on cross-species position data

“…In contrast to Jäger et al. ( 8 ), no distinction was made between species that may extend the length of their telomeres as an adult (replicative aging) and others (non-replicative aging); this is future work.…”

“…This work started with a cross-species cluster analysis based on Ensembl version 99 ( 8 ). With more recent versions (this analysis is based on version 110), the assemblies of genomes have been improved and additional species have been added.…”

“…It is worth noting that, at the time of writing, only six genes have been experimentally verified by 3D-FISH to exhibit TPE-OLD characteristics: C1S, DSP and ISG15 ( 5 ); SORBS2 ( 6 ); TERT ( 7 ) and PPP2R2C ( 8 ). These six known TPE-OLD genes are distributed across different chromosomal arms, hinting at a chromosome-independent mechanism at play.…”

Establishment and Characterization of hTERT Immortalized Hutchinson–Gilford Progeria Fibroblast Cell Lines

“…In HGP primary cells, we found rather a weak inverse correlation between the hTERT mRNA expression and the TL. It is tempting to speculate, but must be examined in detail in other experiments, that this effect may be caused by telomere position effects such as telomere position effect over long distances (TPE-OLD), e.g., the suppression of gene transcription by interference with long telomeres [ 27 ], and that this process might be disturbed in HGP [ 45 ].…”

Combining old and new concepts in targeting telomerase for cancer therapy: transient, immediate, complete and combinatory attack (TICCA)

“…Regular senescence limits the maximum number of cell divisions and may thus limit the probability of tumorigenesis and inhibit the replication of abnormal chromosomes. There is also some evidence that telomere shortening also activates protective genes that have a tumor-suppressive effect [ 13 ] and that this process is disturbed in genetic instability syndromes [ 14 ]. On the other hand, excessive and uncontrolled telomere attrition and telomere damage may also make cells more vulnerable to genomic instability, which then may result in bypassing of the p53/p21/p16/pRb tumor suppressor pathways.…”