Telomere Assignment

7/31/2019 Telomere Assignment

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Telomeres

Telomeres are tandem repeats ((TTAGGG/CCCTAA)n in

vertebrates) that are found at the ends of linear eukaryotic

chromosomes80. Their length varies between chromosomes

and species, but can range from a few to tens of kilobase

pairs. Telomeres have several roles: they prevent the ends of

linear chromosomes from appearing as DNA breaks, they

protect chromosome ends from degradation and fusion, they

allow complete chromosome replication and they position the chromosomes

within the nucleus.

Telomere structure

Telomeres are, through

necessity, dynamic

structures. Although the

ends of the chromosomes

need to be camouflaged to

avoid being seen as DNA

breaks, DNA replication

requires remodelling of this

structure. The repetitive

sequences of telomeres are bound by both duplex-DNA-binding proteins,

which include TRF1 and TRF2 , and single-stranded DNA-binding proteins .
http://www.nature.com/nrc/journal/v1/n3/full/nrc1201-203a.html#B80http://www.nature.com/nrc/journal/v1/n3/full/nrc1201-203a.html#B80http://www.nature.com/nrc/journal/v1/n3/full/nrc1201-203a.html#B80http://www.nature.com/nrc/journal/v1/n3/full/nrc1201-203a.html#B80http://www.clinchem.org/content/43/5/708/F1.expansion.htmlhttp://www.clinchem.org/content/43/5/708/F1.expansion.html


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Telomeres end in a 3' single-strand overhang. The telomere end folds back

on itself, forming a protective 'T-loop', to hide the vulnerable 3' overhang.

This single-stranded DNA invades and hybridizes with a region of the double-

stranded telomere repeat and the displaced DNA forms a small 'D-loop'.

Telomere-binding proteins for example, TRF2, which binds the T-loop

juncture are important in maintaining the stability of this structure (see

upper figure).

Telomere shortening and the end-replication problem

Telomeres shorten in part because of the end replication problem that is

exhibited during DNA replication in eukaryotes only.

Replication of the DNA lagging strand occurs by extension of primers in the 5'

3' direction. At the ends of the chromosomes, the terminal primer on the

lagging strand (3' end) leaves a stretch of DNA that cannot be replicated. As

a result of this, the telomeres shorten by 50200 base pairs with each cell

division. Telomerase is a telomere-specific ribonucleoprotein reverse

transcriptase that adds single-stranded telomeric repeats to the

chromosomal 3' ends, preventing continual telomere shortening.

However, in vitro studies (von Zglinicki et al. 1995, 2000) have shown that

telomeres are highly susceptible to oxidative stress. Telomere shortening due

to free radicals explains the difference between the estimated loss per

division because of the end-replication problem (ca. 20 bp) and actual
http://en.wikipedia.org/wiki/Eukaryotehttp://en.wikipedia.org/wiki/Eukaryote


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telomere shortening rates (50-100 bp), and has a greater absolute impact on

telomere length than shortening caused by the end-replication problem

Telomerase structure

Human telomerase consists of two

molecules each of human telomerase

reverse transcriptase (TERT),

telomerase RNA (TR or TERC), and

dyskerin (DKC1). The genes of

telomerase subunits, which are TERT,

TERC, DKC1, and TEP1 etc, are located

on different chromosomes in the human genome. Human TERT gene (hTERT)

is translated into a protein of 1132 amino acids. TERT proteins from many

eukaryotes have been sequenced. TERT polypeptide folds with TERC, a non-

coding RNA (451 nucleotides long in human). TERT has a 'mitten' structure

that allows it to wrap around the chromosome to add single-stranded

telomere repeats.
http://en.wikipedia.org/wiki/Telomerase_reverse_transcriptasehttp://en.wikipedia.org/wiki/Telomerase_reverse_transcriptasehttp://en.wikipedia.org/wiki/Telomerase_RNA_componenthttp://en.wikipedia.org/wiki/Dyskerinhttp://en.wikipedia.org/wiki/Genomehttp://en.wikipedia.org/wiki/Translation_(genetics)http://en.wikipedia.org/wiki/Proteinhttp://en.wikipedia.org/wiki/Amino_acidshttp://en.wikipedia.org/wiki/Protein_foldinghttp://en.wikipedia.org/wiki/Non-coding_RNAhttp://en.wikipedia.org/wiki/Non-coding_RNAhttp://en.wikipedia.org/wiki/Nucleotidehttp://en.wikipedia.org/wiki/Nucleotidehttp://en.wikipedia.org/wiki/Non-coding_RNAhttp://en.wikipedia.org/wiki/Non-coding_RNAhttp://en.wikipedia.org/wiki/Protein_foldinghttp://en.wikipedia.org/wiki/Amino_acidshttp://en.wikipedia.org/wiki/Proteinhttp://en.wikipedia.org/wiki/Translation_(genetics)http://en.wikipedia.org/wiki/Genomehttp://en.wikipedia.org/wiki/Dyskerinhttp://en.wikipedia.org/wiki/Telomerase_RNA_componenthttp://en.wikipedia.org/wiki/Telomerase_reverse_transcriptasehttp://en.wikipedia.org/wiki/Telomerase_reverse_transcriptase


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Telomerase function

By using TERC, TERT can add a six-nucleotide

repeating sequence, 5'-TTAGGG (in all

vertebrates, the sequence differs in other

organisms) to the 3' strand of chromosomes.

These TTAGGG repeats (with their various

protein binding partners) are called

telomeres. The template region of TERC is 3'-

CAAUCCCAAUC-5'.[12] This way, telomerase

can bind the first few nucleotides of the

template to the last telomere sequence on

the chromosome, add a new telomere repeat

(5'-GGTTAG-3') sequence, let go, realign the

new 3'-end of telomere to the template, and repeat the process. (For an

explanation on why this elongation is necessary see Telomere shortening.)

ALT pathway of telomeres

In most human somatic cells, telomerase activity is very low. This leads to

gradual telomere shortening which, in turn, can trigger replicative

senescence, a process where a cell with critically short telomeres

permanently exits from the cycle of division. In contrast, the great majority

of cancers are able to maintain their telomere lengths indefinitely. In most

cases, this occurs because of an up-regulation of telomerase activity.
http://en.wikipedia.org/wiki/Telomerase#cite_note-pmid12384594-11http://en.wikipedia.org/wiki/Telomere#Telomere_shorteninghttp://en.wikipedia.org/wiki/Cellular_senescencehttp://en.wikipedia.org/wiki/Cellular_senescencehttp://en.wikipedia.org/wiki/Cell_cyclehttp://en.wikipedia.org/wiki/Cell_cyclehttp://en.wikipedia.org/wiki/Cellular_senescencehttp://en.wikipedia.org/wiki/Cellular_senescencehttp://en.wikipedia.org/wiki/Telomere#Telomere_shorteninghttp://en.wikipedia.org/wiki/Telomerase#cite_note-pmid12384594-11


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However, some cancers maintain their telomere lengths through a

telomerase-independent process termed alternative lengthening of telomeres

(ALT). The telomeres in ALT cells are highly heterogeneous, often extremely

long and appear to be maintained through homologous recombination.

Telomeres , the Hayflick limit and Cell Immortality

The Hayflick limit (or Hayflick Phenomenon) is the number of times a normalcell population will divide before it stops, presumably because the telomeresshorten to a critical length.

The Hayflick limit was discovered by Leonard Hayflick in 1961, at the WistarInstitute, Philadelphia, when Hayflick demonstrated that a population ofnormal human fetal cells in a cell culture divide between 40 and 60 times. Itthen enters a senescence phase (refuting the contention by Alexis Carrel thatnormal cells are immortal). Each mitosis shortens the telomeres on the DNAof the cell. Telomere shortening in humans eventually makes cell divisionimpossible, and it correlates with aging. This mechanism appears to preventgenomic instability and the development ofcancer.

In cultured cells, the loss of telomeric DNA depends on the number of celldivisions, and Allsopp et al. have noted that telomere length is a usefulpredictor of the residual proliferative capacity of cells . In this context, thequestion arises as to whether one could achieve unlimited replicationcapacity and immortality in somatic cells if telomere length could bemaintained. Counter et al. transfected normal human embryonic kidney cellswith Simian Virus 40 tumor antigen (SV 40 T), forming a tumor virus proteinthat extended the lifespan of cultured cells. The transfected cells divided andentered a point of crisis, in which most of the cells died; only some cellsbecame immortal. During the period of cell division, the telomeres shortenedcontinually and no telomerase activity could be detected. Those cells thatsurvived the crisis point and became immortal had reactivated telomeraseand stabilized their telomeres. This means that even somatic cells can gainthe ability of endless replication if telomere length is maintained and (or) the

enzyme telomerase is activated.

Cells in culture are thought to stop dividing because of activation of anantiproliferative mechanism termed mortality stage 1 (M1). The stimulusfor the induction of M1 may be DNA-damage signals from the alteredexpression of subtelomeric regulatory genes or from a critical shortenedtelomere. P53 and the retinoblastoma gene product pRb are involved in theexecution of M1. One hypothesis for the induction of M1 postulates thefollowing: (a) a single chromosome denuded of telomeric repeats produces a
http://en.wikipedia.org/wiki/Heterogeneoushttp://en.wikipedia.org/wiki/Homologous_recombinationhttp://en.wikipedia.org/wiki/Telomereshttp://en.wikipedia.org/wiki/Leonard_Hayflickhttp://en.wikipedia.org/wiki/Wistar_Institutehttp://en.wikipedia.org/wiki/Wistar_Institutehttp://en.wikipedia.org/wiki/Philadelphiahttp://en.wikipedia.org/wiki/Humanhttp://en.wikipedia.org/wiki/Fetushttp://en.wikipedia.org/wiki/Cell_culturehttp://en.wikipedia.org/wiki/Senescence#Cellular_senescencehttp://en.wikipedia.org/wiki/Alexis_Carrelhttp://en.wikipedia.org/wiki/Biological_immortalityhttp://en.wikipedia.org/wiki/Mitosishttp://en.wikipedia.org/wiki/Telomereshttp://en.wikipedia.org/wiki/Cancerhttp://en.wikipedia.org/wiki/Cancerhttp://en.wikipedia.org/wiki/Telomereshttp://en.wikipedia.org/wiki/Mitosishttp://en.wikipedia.org/wiki/Biological_immortalityhttp://en.wikipedia.org/wiki/Alexis_Carrelhttp://en.wikipedia.org/wiki/Senescence#Cellular_senescencehttp://en.wikipedia.org/wiki/Cell_culturehttp://en.wikipedia.org/wiki/Fetushttp://en.wikipedia.org/wiki/Humanhttp://en.wikipedia.org/wiki/Philadelphiahttp://en.wikipedia.org/wiki/Wistar_Institutehttp://en.wikipedia.org/wiki/Wistar_Institutehttp://en.wikipedia.org/wiki/Leonard_Hayflickhttp://en.wikipedia.org/wiki/Telomereshttp://en.wikipedia.org/wiki/Homologous_recombinationhttp://en.wikipedia.org/wiki/Heterogeneous


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DNA-damage signal, which (b) induces p53 and p21; (c) p21 inhibits thecyclin-dependent kinases, which then (d) are prevented fromphosphorylating pRb; (e) the presence of unphosphorylated pRb coupled withother actions of p53 and p21 results in the M1 arrest (21). If these cell cycleregulators are mutated or blocked, the cells continue to divide and thus thetelomeres continue to shorten. Cells divide until a second independent blockin proliferation is reached, termed mortality stage 2 (M2). The M2mechanism is probably induced when so few telomere repeats remain thatthe unprotected chromosomal ends block further proliferation. The M2 blockmight be overcome in some cells by reactivation of telomerase, the repair ofchromosome ends, the stabilization of telomere length, and the generation ofan immortal cell clone .
http://www.clinchem.org/content/43/5/708.full#ref-21http://www.clinchem.org/content/43/5/708/F3.expansion.htmlhttp://www.clinchem.org/content/43/5/708.full#ref-21


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Telomeres , Stress and Aging

A major cause of aging is "oxidative stress." It is the damage to DNA,proteins and lipids (fatty substances) caused by

oxidants, which are highly reactive substancescontaining oxygen. These oxidants are producednormally when we breathe, and also result frominflammation, infection and consumption ofalcohol and cigarettes. In one study, scientistsexposed worms to two substances thatneutralize oxidants, and the worms' lifespanincreased an average 44 percent.

Another factor in aging is "glycation." It happenswhen glucose sugar from what we eat binds tosome of our DNA, proteins and lipids, leaving

them unable to do their jobs. The problembecomes worse as we get older, causing bodytissues to malfunction, resulting in disease and death. This may explain whystudies in various laboratory animals indicate that restricting calorie intakeextends lifespan.

It is possible oxidative stress, glycation, telomere shortening andchronological age - along with various genes - all work together to causeaging.

Geneticist Richard Cawthon and colleagues at the University of Utah foundshorter telomeres are associated with shorter lives. Among people older than

60, those with shorter telomeres were three times more likely to die fromheart disease and eight times more likely to die from infectious disease.

It was also found that in patients with syndromes of accelerated aging[progeria (i.e., HutchinsonGilford syndrome) and Werner syndrome], themean telomere lengths in cell cultures were considerably shorter than innormal individuals. These premature aging syndromes are characterized inprogeria by growth retardation and accelerated degenerative changes of thecutaneous, musculoskeletal, and cardiovascular systems in young patients ,and in Werner syndrome, for which recently the a candidate gene has been

identified , by an early-onset and accelerated rate of development of majorgeriatric disorders such as atherosclerosis, diabetes mellitus, osteoporosis,and various neoplasms .


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The new findings also suggest that chronic stress, and the perception of life

stress, each had a significant impact on three biological factors -- the length

of telomeres, the activity of telomerase, and levels of oxidative stress -- in

immune system cells known as peripheral blood mononucleocytes, in healthy

premenopausal women.

At Harvard, they bred genetically manipulated mice that lacked an enzymecalled telomerase that stops telomeres getting shorter. Without the enzyme,the mice aged prematurely and suffered ailments, including a poor sense ofsmell, smaller brain size, infertility and damaged intestines and spleens. Butwhen DePinho gave the mice injections to reactivate the enzyme, it repairedthe damaged tissues and reversed the signs of ageing .The key question is

what might this mean for human therapies against age-related diseases?While there is some evidence that telomere erosion contributes to age-associated human pathology, it is surely not the only, or even dominant,cause, as it appears to be in mice engineered to lack telomerase.

Furthermore, there is the ever-present anxiety that telomerase reactivationis a hallmark of most human cancers."

Telomeres, telomerase, and cancer

The cell cycle includes the orderly sequence of events that ensure the faithfulduplication of all the cellular components in their correct sequence and thepartitioning of these components into two daughter cells. Two classes ofgenes and their protein products are used to accomplish this process: geneswhose products are obligatory for progress through the cell cycle phases, andgenes whose proteins act as checkpoints for monitoring the efficacy andcompletion of these obligatory events and stopping the progression throughthe cell cycle if conditions are not satisfactory. The loss of cell cycle controlgenerally leads to cell death but can also result in abnormal cells thatcontinue to replicate and eventually form a tumor . The theory ofcarcinogenesis suggests that unlimited cell proliferation is required fordevelopment of malignant disease, and cancer cells must attain immortalityfor progression to malignant states. As shown above, shortening of telomeresmay contribute to the control of the proliferative capacity of normal cells, andthe enzyme telomerase may be essential for unlimited cell proliferation.

The length of telomeres in cancer cells depends on a balance between thetelomere shortening at each cell cycle and the telomere elongation resultingfrom telomerase activity. Tumors with shorter telomeres than in the originaltissue have been detected in many cancer types . In neuroblastoma,endometrial cancer, breast cancer, leukemias, and lung cancer, a correlationbetween decreasing telomere lengths and an increasing severity of diseasehas been described. Short telomeres seem to be a primary cause forkaryotype instability in malignant cells. According to the above-describedtheory of telomere dynamics during cell progression, tumor cells with


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shortened telomeres can be considered to have undergone many celldivisions, with an accumulation of various genetic alterations. After a point ofcritical telomere shortening, telomerase might be reactivated to stabilize orelongate the telomeric DNA.

Tumors with telomeres just as long as or even longer than in the original

tissue seem to be rarer but have been described in some human malignanttissues, e.g., intracranial tumors, basal cell carcinomas of the skin, and renal

cell carcinomas . There are two possible explanations for this phenomenon:Either an activated telomerase has elongated the once-shortened telomeresback to former length, or the tumor cells have not yet undergone enough celldivisions to induce significant shortening of telomeres.

Telomerase is absent in most human somatic cells but, as Rhyu reports , was

detected in 85% of 400 tumor tissue samples. Low amounts of telomeraseactivity in normal human tissues were found only in hematopoietic progenitorcells and activated T- and B-lymphocytes ; in germ cells, ovaries, and testes;and in physiologically regenerating epithelial cells . Results fromexaminations of normal tissues and benign cancers as well as malignantprimary and metastatic tumors permit several conclusions. As in most normaltissues, telomerase activity is not expressed in somatic tissues adjacent tothe tumor tissue. Accordingly, telomerase activity has proved to be a reliablemarker for detecting tumor cells in resection margins.

In benign and premalignant tumors, including breast fibrocystic disease andfibroadenomas, benign prostatic hyperplasia, colorectal adenomas, anaplasticastrocytomas, and benign meningiomas and leiomyomas, in general notelomerase activity was detected; however, it was found in malignant tumorstages . In this way, telomerase activity is associated with the acquisition of

malignancy. The detection of telomerase activity at preneoplastic or benigngrowth stages may signify disease progression and be of diagnostic value.For example, telomerase activity has been found in some cases of benignprostate hyperplasia and of benign giant tumors of the bone - all tissues thatmay progress to malignant tumors.

As shown by Hiyama et al. in breast cancer, telomerase provides a usefuldiagnostic tumor marker: Among samples obtained by fine-needle aspiration,14 of 14 patients whose aspirates contained detectable telomerase activity,and who subsequently underwent surgery, were confirmed to have breastcancer.

Certain tumor types, such as neuroblastoma, display a lower telomeraseactivity in early-stage cancers, whereas expression in late-stage cases ishigher. Neuroblastomas of a special stage (stage IV), which had shorttelomeres and no or weak telomerase activity, tended to regressspontaneously possible proof of a correlation between an enzyme activitytoo weak to remain in an immortal tumor status and a favorable outcome forthe patient.


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Another example of telomerase activity in cancer diagnosis and as aprognostic indicator of clinical outcome is the results found in gastric cancers.Hiyama et al. showed that the survival rate of patients with tumors withdetectable telomerase activity in their study was shorter than that of thosewithout telomerase activity.

Although a reliable tumor marker, telomerase activity is not an all-or-nonephenomenon. To understand the regulation of telomerase during

tumorigenesis, Greider et al. analyzed the concentrations of telomerase RNAcomponents and discussed the differential regulation of enzyme activityaccording to the concentration of the RNA component .

Further prospective and retrospective clinical studies must be carried out toassess the validity of telomere dynamics and telomerase as a diagnostic or

prognostic marker in many cancer types.

Up-Regulation of Telomere-Binding Proteins, TRF1, TRF2, and

TIN2 is Related to Telomere Shortening during HumanMultistep Hepatocarcinogenesis

The telomeric repeat-binding factor 1 (TRF1), TRF2, and the TRF1-interacting

nuclear protein 2 (TIN2) are involved in telomere maintenance. We describe

the regulation of expression of these genes along with their relationship to

telomere length in hepatocarcinogenesis. The transcriptional expression of

these genes, TRF1 protein, and telomere length was examined in 9 normallivers, 14 chronic hepatitis, 24 liver cirrhosis, 5 large regenerative nodules,

14 low-grade dysplastic nodules (DNs), 7 high-grade DNs, 10 DNs with

hepatocellular carcinoma (HCC) foci, and 31 HCCs. The expression of TRF1,

TRF2, TIN2 mRNA, and TRF1 protein was gradually increased according to

the progression of hepatocarcinogenesis with a marked increase in high-

grade DNs and DNs with HCC foci and a further increase in HCCs. There was

a gradual shortening of telomere during hepatocarcinogenesis with a

significant reduction in length in DNs. Most nodular lesions (52 of 67) had

shorter telomeres than their adjacent chronic hepatitis or liver cirrhosis, and

the telomere lengths were inversely correlated with the mRNA level of thesegenes (P 0.001). This was more evident in DNs and DNs with HCC foci. In

conclusion, TRF1, TRF2, and TIN2 might be involved in multistep

hepatocarcinogenesis by playing crucial roles in telomere shortening.


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Telomerase as a target for anticancer therapy

These findings suggest that reactivation of telomerase may be an obligateevent in cell immortalization and in most instances of tumorigenesis. Anykind of inhibition of the enzyme should therefore lead to resumption oftelomere shortening and might activate the cellular senescence pathway. Thefact that telomerase is absent and not required in most human somatictissues but is necessary for tumor growth should make this enzyme an idealtarget for anticancer therapy.

One of the greatest challenges in cancer therapy is to achieve a hightherapeutic effect by maximizing the desired reactions and minimizing theundesired side-effects. Several conditions must be successfully fulfilled toachieve a beneficial antitumor effect in vivo:

1) Introduction of the antitumor agent into the majority and perhaps 100%of the tumor cells

2) The antitumor agent reaching the target

3) Tumor cell death

4) Acceptable toxicity to normal cells

5) Absence of a deleterious host immune response.

One of the most hopeful approaches to achieving these goals isoligonucleotide-based gene therapy. The regulation of expression of geneticinformation by complementary pairing of sense and antisense nucleic acidstrands has been termed antisense. It is now possible to design antisenseDNA oligonucleotides or antisense RNAs that can pair with and functionally

inhibit the expression of genes in a sequence fashion. This high degree ofspecificity has made antisense constructs attractive candidates fortherapeutic agents . Because the antisense sequences require chemicalmodifications to avoid destruction by nucleases and to form complexes forbetter delivery into the cell, peptide nucleic acids (PNAs) have beendesignedwith a charge-neutral, pseudo-peptide backbone of N-(2-aminoethyl)glycine units instead of a negatively charged deoxyribose-phosphate backbone .

Recently, Norton et al. reported on PNAs that have a sequencecomplementary to the RNA component of human telomerase. They designedoligonucleotides that bind to the RNA molecule within the telomerase, whichserves as the enzymes own internal telomere template. These moleculesseem to be very specific and efficient inhibitors of telomerase in vitro.Further experiments with cell cultures and tumor models in mice will continuethis path of investigation and could justify the optimism surrounding thetelomerase hypothesis and its exploitation as a novel anti-cancer therapy.


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Several important unanswered questions remain. A possible therapeuticapproach of telomerase to cancer patients would appear to be less toxic thanconventional chemotherapy, which affects all dividing cells and hasundesirable side effects. However, some normal somatic cells aretelomerase-positive at baseline: human hematopoietic progenitor cells, germcells (progenitors of sperm and oocytes), and activated T-and B-lymphocytes. Telomeric DNA in these cells would be lost during an anti-telomerase therapy. Perhaps this loss could be buffered, because of thelonger telomeres in these cells than in cancer cells and because of the lowerdivision rate relative to tumor cells. Another problem is in the variability oftelomere lengths among tumors. Telomerase inhibition seems to be usefulonly in malignant cells with short telomeres; tumor cells with long telomereswould require a prolonged treatment, with possible toxic side-effects. Oneshould also consider that alternative pathways besides telomerase may existfor regulating telomere length.

Many other issues remain to be resolved. Even if the causal relationship were

clear between continually shrinking telomeres and cellular senescence on theone side and unlimited proliferation of cells that have stabilized theirtelomeres length by the enzyme telomerase on the other, we still need to learn: Which genes encode telomerase components? Are telomeric RNA andproteins regulated at the transcriptional or posttranscriptional level? Doesregulation of the RNA or of the protein components determine activity? Dointernal cellular mechanisms exist to repress telomerase? Based on thepresent knowledge of telomeres and telomerase mechanisms, considerableefforts will have to be taken to answer these open questions and to make useof the new results for developing new diagnostic tools and therapeuticstrategies.


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References

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2. Passarge, Eberhard. Color atlas of genetics, 2007.3. Allsopp RC, Vaziri H, Patterson C, Goldstein S, Younglai EV, Futcher AB, GreiderCW, Harley CB. Telomere length predicts replicativecapacity of human fibroblasts.

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