Telomere dysfunction and tumour suppression: the senescence connection

Abstract

Long lived organisms such as humans have evolved several intrinsic tumor suppressor mechanisms to combat the slew of oncogenic somatic mutations that constantly arise in proliferating stem cell compartments. One of these anti-cancer barriers is the telomere, a specialized nucleoprotein that caps the ends of eukaryotic chromosome. Impaired telomere function activates the canonical DNA damage response pathway that engages p53 to initiate apoptosis or replicative senescence. Here, we discuss how p53-dependent senescence induced by dysfunctional telomeres may be as potent as apoptosis in suppressing tumorigenesis in vivo.More than 40 years ago, Hayflick and Moorhead discovered that normal human diploid fibroblasts (HDFs) cannot grow indefinitely in culture 1 . Rather, their proliferative capacities are intrinsically limited. After 60-80 population doublings in culture, HDFs stop dividing and adopt a phenotype characterized by large, flat cell size, a vacuolated morphology, inability to synthesize DNA, and the presence of the senescence-associated β-galactosidase (SA-β-gal) marker 2 . We now know that the endpoint of this proliferative limit, termed replicative senescence, is due largely to erosion of telomeres, protective structures that cap the end of all eukaryotic chromosomes. Confirmation of this came from studies in which telomerase, the enzyme that maintains telomeres, was ectopically expressed in normal human somatic cells 3,4 . Activation of telomerase results in telomere elongation, abrogation of replicative senescence, a normal karyotype and cellular immortalization. These results clearly demonstrate that telomere length determines the proliferative lifespan of HDFs, and that upregulation of telomerase activity (hence telomere length) restores proliferative capacity.A large body of experimental evidence has demonstrated that telomere attrition contributes to tumorigenesis by promoting genome instability 5 . However, in the setting of a competent p53 pathway, mouse models have recently shown that telomere shortening is also tumor suppressive by promoting replicative senescence to inhibit tumor formation. In this Perspective, we will discuss how telomeres shorten with cell replication and how this might initiate a DNA damage response to induce replicative senescence (and cell death) and ultimately prevent tumorigenesis.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) induces cancer cell senescence by interacting with telomerase RNA component

“…2 B and C). To determine whether elevated GAPDH gene expression might potentially alter the gene expression of hTERT, the catalytic subunit and rate-limiting component of telomerase (32,33), we measured hTERT gene expression by real-time PCR and found that there were no significant changes in the hTERT gene expression levels (Fig. 2D).…”

A population of BJ fibroblasts escaped from Ras-induced senescence susceptible to transformation

“…This type of senescence, termed replicative senescence, is caused by the shortening of a telomere, which is a protective structure capping the end of eukaryotic chromosomes [2].…”

Tumor Cell Development: A Role for Viruses and Telomerase Activity?

“…10 The accumulation of such shortening results in loss of telomeric DNA and, eventually, los of chromosome capping, which triggers p53-mediated senescence and/or apoptosis, thus limiting lifespan at the cellular level. 11 Telomere shortening is counteracted by telomerase activity. This ribonucleoprotein complex is composed of two main subunits: the telomerase reverse transcriptase (TERT, encoded by TERT; GeneEntrez ID: 7015), which promotes telomere elongation by reverse transcription, and the telomerase AdvAnces in Tumor virology 2014: 4 RNA component (TERC, encoded by TERC; GeneEntrez ID: 7012), which serves as a template for the reaction.…”