Category — stem cell

Ilaria Chiodi and Chiara Mondello*
Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Pavia, Italy
Telomerase canonical activity at telomeres prevents telomere shortening, allowing chromosome stability and cellular proliferation. To perform this task, the catalytic subunit (telomerase reverse transcriptase, TERT) of the enzyme works as a reverse transcriptase together with the telomerase RNA component (TERC), adding telomeric repeats to DNA molecule ends. Growing evidence indicates that, besides the telomeric-DNA synthesis activity, TERT has additional functions in tumor development and is involved in many different biological processes, among which cellular proliferation, gene expression regulation, and mitochondrial functionality. TERT has been shown to act independently of TERC in the Wnt-β-catenin signaling pathway, regulating the expression of Wnt target genes, which play a role in development and tumorigenesis. Moreover, TERT RNA-dependent RNA polymerase activity has been found, leading to the genesis of double-stranded RNAs that act as precursor of silencing RNAs. In mitochondria, a TERT TERC-independent reverse transcriptase activity has been described that could play a role in the protection of mitochondrial integrity. In this review, we will discuss some of the extra-telomeric functions of telomerase.
Keywords: telomerase, TERT, telomere, transformation, cancer, apoptosis, mitochondria, RNA interference
Citation: Chiodi I and Mondello C (2012) Telomere-independent functions of telomerase in nuclei, cytoplasm, and mitochondria. Front. Oncol. 2:133. doi: 10.3389/fonc.2012.00133
Received: 31 July 2012; Accepted: 18 September 2012;
Published online: 28 September 2012.
Edited by:
Claus M. Azzalin, Eidgenössische Technische Hochschule Zürich, Switzerland
Susan M. Bailey, Colorado State University, USA
Reviewed by:
Xu-Dong Zhu, McMaster University, Canada
Yongmei Song, Chinese Academy of Medical Sciences and Peking Union Medical College, China
Copyright: © 2012 Chiodi and Mondello. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
*Correspondence: Chiara Mondello, Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Via Abbiategrasso 207, 27100 Pavia, Italy. e-mail: mondello@igm.cnr.it

By John Gever, Senior Editor, MedPage Today
Published: September 21, 2010
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Shortened telomeres in peripheral blood leukocytes may predict relapse, malignant progression, and poorer survival in patients with severe aplastic anemia, researchers at the National Institutes of Health (NIH) reported.

An analysis of average pretreatment telomere length in almost 200 patients with severe aplastic anemia treated at the NIH, revealed that patients in the first quartile for telomere length — the shortest telomeres — had an overall six-year survival rate of 66% (95% CI 52.9% to 82.5%) compared with 83.8% (95% CI 77.3% to 90.0%) among those in the other three quartiles (P=0.008), according to the Sept. 22 issue of the Journal of the American Medical Association.

Having the shortest telomeres was also associated with greater risk of progression to malignancy (24.5% versus 8.4%, P=0.009) and with evolution to monosomy 7 or complex cytogenetics (18.8% versus 4.5%, P=0.002), wrote Phillip Scheinberg, MD, of the National Heart, Lung, and Blood Institute in Bethesda, Md., and colleagues.

“Clonal evolution to myelodysplasia is a major adverse event in severe aplastic anemia; it cannot be routinely predicted and usually signals a poor prognosis,” Scheinberg and colleagues noted.

They suggested their findings point toward a practical method of identifying patients at heightened risk for progression who might receive more aggressive treatment.

“Higher-risk protocols such as stem cell transplants in older patients and alternative sources of stem cells might be considered earlier in younger patients,” the researchers wrote.

They also indicated that androgen treatment may lengthen telomeres, potentially altering patients’ risk profiles.

Telomeres are the protective end-caps on chromosomes. Portions are lopped off with each round of cell division, although they may be restored by the telomerase enzyme complex.

Cell senescence has been associated with critically short telomeres, but mutations in telomerase genes that result in extremely short telomeres have been found in some patients with severe aplastic anemia.

Scheinberg and colleagues measured telomere lengths in pretreatment peripheral blood samples from 183 patients treated for severe aplastic anemia at the NIH from 2000 to 2008.

They found no relationship between telomere length and initial treatment responses. Hematologic response rates were nearly identical in each quartile of telomere length, ranging from 54% to 60%.

But the subsequent course for patients in the first quartile — those with the shortest telomeres — differed significantly over as long as six years from patients in the second to fourth quartiles — those with longer telomeres.

By far the worst survival outcomes were in first-quartile patients who also had absolute reticulocyte counts below 25,000 per μL.

With four years of follow-up, just over 50% of these patients were still alive. The four-year survival rate among those in the first quartile but higher reticulocyte counts, and those with low counts but longer telomeres, was close to 80%.

Nearly all of those with longer telomeres and high reticulocyte counts survived at least four years. Few deaths occurred in study patients after year four irrespective of telomere or reticulocyte status.

For other outcomes — hematologic relapse, clonal evolution, progression to monosomy 7 or complex cytogenetics — differences according to telomere length were apparent in about two years.

Scheinberg and colleagues asserted that truncated telomeres are “not simply a biomarker,” but may play a direct role in the disease process.

“Ample in vitro and animal experimentation indicate that critical shortening of telomeres causes chromosome instability, tumor formation, and cancer progression,” they wrote.

Although short telomeres would ordinarily lead to senescence, the chromosomal damage that may result from defective end-caps may instead allow cells to turn malignant, especially if they also lack functional p53 or other tumor suppressor mechanisms, the researchers suggested.

Scheinberg and colleagues noted some limitations of their study. Its retrospective nature was one; another was the relatively small number of patients that precluded assembling a separate validation cohort. They also noted that the NIH patient pool may not be representative of patients elsewhere.

“Our results need to be replicated to validate the observed associations and to determine reliable telomere length thresholds that could be incorporated in treatment algorithms,” the researchers concluded.

The study was funded by the National Heart, Lung, and Blood Institute.

One author obtained salary support from a training program partially funded by Pfizer.

The authors declared they had no relevant financial interests.

Primary source: Journal of the American Medical Association
Source reference:
Scheinberg P, et al “Association of telomere length of peripheral blood leukocytes with hematopoietic relapse, malignant transformation, and survival in severe aplastic anemia” JAMA 2010; 304: 1358-1364.

Siegl-Cachedenier I, Flores I, Klatt P, Blasco MA. J Cell Biol. ;179(2):277-90.

Organ homeostasis and organismal survival are related to the ability of stem cells to sustain tissue regeneration. As a consequence of accelerated telomere shortening, telomerase-deficient mice show defective tissue regeneration and premature death. This suggests a direct impact of telomere length and telomerase activity on stem cell biology. We recently found that short telomeres impair the ability of epidermal stem cells to mobilize out of the hair follicle (HF) niche, resulting in impaired skin and hair growth and in the suppression of epidermal stem cell proliferative capacity in vitro. Here, we demonstrate that telomerase reintroduction in mice with critically short telomeres is sufficient to correct epidermal HF stem cell defects. Additionally, telomerase reintroduction into these mice results in a normal life span by preventing degenerative pathologies in the absence of increased tumorigenesis.

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H. Jiang, Z. Ju, K.L. Rudolph; Z Gerontol Geriat 40:314-324; 2007

Telomeres form the ends of human chromosomes. Telomeres shorten with each round of cell division and this mechanism limits proliferation of human cells to a finite number of cell divisions by inducing replicative senescence, differentiation, or apoptosis. Telomere shortening can act as a tumor suppressor. However, as a downside, there is growing evidence indicating that telomere shortening also limits stem cell function, regeneration, and organ maintenance during ageing. Moreover, telomere shortening during aging and disease is associated with increasing cancer risk. In this review we summarize our current knowledge on the role of telomere shortening in human ageing, chronic diseases, and cancer.

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E Hiyama and K Hiyama, British Journal of Cancer 96, 1020-1024.

Telomeres, guanine-rich tandem DNA repeats of the chromosomal end, provide chromosomal stability, and cellular replication causes their loss. In somatic cells, the activity of telomerase, a reverse transcriptase that can elongate telomeric repeats, is usually diminished after birth so that the telomere length is gradually shortened with cell divisions, and triggers cellular senescence. In embryonic stem cells, telomerase is activated and maintains telomere length and cellular immortality; however, the level of telomerase activity is low or absent in the majority of stem cells regardless of their proliferative capacity. Thus, even in stem cells, except for embryonal stem cells and cancer stem cells, telomere shortening occurs during replicative ageing, possibly at a slower rate than that in normal somatic cells. Recently, the importance of telomere maintenance in human stem cells has been highlighted by studies on dyskeratosis congenital, which is a genetic disorder in the human telomerase component. The regulation of telomere length and telomerase activity is a complex and dynamic process that is tightly linked to cell cycle regulation in human stem cells. Here we review the role of telomeres and telomerase in the function and capacity of the human stem cells.

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