Category Archives: Telomere and Telomerase

Long Telomere Leads to Health or Brain Cancer?

When I hear that some gene, or protein has the potential to prolong our life, I am doubled very much. Our bodies wear out and any effort to reverse this biological process risks turning up cancer. As the telomere caps on chromosome ends wear down, Cells would lose the ability to divide. So longer telomere caps good? Shorter telomere caps bad? It’s not that easy.


A new research conducted by UC San Francisco (UCSF) scientists reveals that 2 common gene variants link to long telomeres, the caps on chromosome generally thought to be a sign of slow biological ageing, also raise the risk of deadly brain cancers known as gliomas.

Identify “culprit” gene

In this research, researchers analyzed genome-wide data from 1,644 glioma patients and 7,736 healthy control individuals, including some who took part in The Cancer Genome Atlas project sponsored by the National Cancer Institute and National Human Genome Research Institute. This work identify risk alleles for glioma near TERC and TERT that also associate with telomere length.

The genetic variants, in the TERT and TERC genes known to regulate the action of telomerase, are respectively carried by 51% and 72% of the population. Because it is somewhat unusual for such risk-conferring variants to be carried by a majority of people, the researchers propose that in these carriers the overall cellular robustness afforded by longer telomeres trumps the increased risk of high-grade gliomas, which are invariably fatal but relatively rare cancers.

“Though longer telomeres might be good for you as a whole person, reducing many health risks and slowing aging, they might also cause some cells to live longer than they’re supposed to, which is one of the hallmarks of cancer,” said lead author Kyle M. Walsh, PhD, assistant professor of neurological surgery and a member of the Program in Cancer Genetics at UCSF’s Helen Diller Family Comprehensive Cancer Center.

Previous Research on telomere 

UCSF’s Elizabeth Blackburn, PhD, shared the 2009 Nobel Prize in Physiology or Medicine for her pioneering work on telomeres and telomerase, an area of research she began in the mid-1970s. In the ensuing decades, untangling the relationships between telomere length and disease has proved to be complex.

In much research, longer telomeres have been considered a sign of health — for example, Blackburn and others have shown that individuals exposed to chronic stressful experiences have shortened telomeres. But because cancer cells promote their own longevity by maintaining telomere length, drug companies have searched for drugs to specifically target and block telomerase in tumors in the hopes that cancer cells will accumulate genetic damage and die.

In some of these cases, the disease-associated variants promote longer telomeres, and in others shorter telomeres, suggesting that “both longer and shorter telomere length may be pathogenic, depending on the disease under consideration,” the authors write.


1. Variants near TERT and TERC influencing telomere length are associated with high-grade glioma risk. Nature Genetics on June 8, 2014

2. Telomeres and telomerase: their mechanisms of action and the effects of altering their functions. FEBS Lett. 2005 Feb 7;579(4):859-62.

Noncanonical Functions of Telomerase and Telomerase-Targeted Cancer Therapies

Telomerase plays a key role in bypassing cellular senescence and maintaining telomere homeostasis, essential properties required for the sustenance and progression of cancer. However, recent researches have uncovered noncanonical properties of telomerase that are independent of its role in telomere extension. The following picture is the human telomerase structure model.


As we know, telomerase consists of TERT subunit, RNA subunit and a group of accessory protein , repaires chromosomal shrinkage resulting from the “end-replication” problem. It plays the critical role in maintaining the balance between normal cellular differentiation and the aberrant proliferation manifested in carcinogenic transformation.

Recently, researchers proposed a model of the feed-forward regulatory loop underscoring the interaction of TERT with the Wnt/β-catenin and NF-κB signaling pathways during cancer development. Reactivated TERT acts as a transcriptional modulator of Wnt/β-catenin and NF-κB signaling, resulting in the enhanced expression of Wnt and NF-κB target genes that exert cancer-promoting functions such as proliferation, resistance to apoptosis, and chronic inflammation. As Wnt/β-catenin and NF-κB are also transcriptional activators of TERT, the researchers suggest a feed-forward pathway (illustrated by blue arrows) that sustains Wnt/β-catenin and NF-κB–dependent transcription as well as levels of telomerase in cancer cells in a simplified schematic of signaling events.


 In view of the evidence mentioned earlier linking the noncanonical functions of telomerase to cancer development and progression, targeting telomerase as an anticancer strategy seems to be an effective approach to simultaneously dampen oncogenic signaling pathways that are augmented by telomerase and disrupt the feed-forward regulatory mechanism driving chronic inflammatory/oncogenic responses and sustained telomerase activity in cancers. Furthermore, as telomerase is often upregulated in cancer cells, whereas majority of normal somatic cells have undetectable telomerase activities, telomerase-targeted cancer therapies serve to selectively eliminate tumor cells and avoid the adverse side effects. More and more evidence indicates a compelling rationale for the development of therapeutic approaches that target the noncanonical roles of telomerase, instead of solely relying on conventional small-molecule inhibitors that restrict its enzymatic activity or accessibility/function at telomeres.

 Marian R.Glancy


1. Noncanonical functions of telomerase: implications in telomerase-targeted cancer therapies.    Cancer Res. 2014 Mar 15;74(6):1639-44.

2. Structural basis for telomerase catalytic subunit TERT binding to RNA template and telomeric    DNA. Nat Struct Mol Biol. 2010 Apr;17(4):513-8

3. Human telomerase model shows the role of the TEN domain in advancing the double helix for the next polymerization step. Proc Natl Acad Sci U S A. 2011 Jun 7;108(23):9443-8

4. Telomerase modulates Wnt signalling by association with target gene chromatin. Nature. 2009 Jul 2;460(7251):66-72.

5. Wnt/β-catenin signaling regulates telomerase in stem cells and cancer cells. Science. 2012 Jun 22;336(6088):1549-54.

6. Telomerase directly regulates NF-κB-dependent transcription. Nat Cell Biol. 2012 Dec;14(12):1270-81.