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Telomerase, also called terminal transferase,[1] is a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of telomeres. A telomere is a region of repetitive sequences at each end of eukaryotic chromosomes in most eukaryotes. Telomeres
Telomeres
protect the end of the chromosome from DNA damage or from fusion with neighbouring chromosomes. The fruit fly Drosophila melanogaster
Drosophila melanogaster
lacks telomerase, but instead uses retrotransposons to maintain telomeres.[2] Telomerase
Telomerase
is a reverse transcriptase enzyme that carries its own RNA molecule (e.g., with the sequence 3′-CCCAAUCCC-5′ in Trypanosoma brucei)[3] which is used as a template when it elongates telomeres. (Beyond unicellular organisms) Telomerase
Telomerase
is active in normal stem cells and most cancer cells, but is normally absent from, or at very low levels in, most somatic cells.

Contents

1 History 2 Human telomerase structure 3 Mechanism 4 Clinical implications

4.1 Aging

4.1.1 Premature aging

4.2 Cancer

4.2.1 Drugs 4.2.2 Immunotherapy 4.2.3 Telomerase
Telomerase
Vaccines 4.2.4 Targeted apoptosis 4.2.5 Small interfering RNA
RNA
(siRNA)

4.3 Heart disease, diabetes and quality of life 4.4 Rare human diseases

5 See also 6 References 7 Further reading 8 External links

History[edit] The existence of a compensatory mechanism for telomere shortening was first found by Soviet biologist Alexey Olovnikov in 1973,[4] who also suggested the telomere hypothesis of aging and the telomere's connections to cancer. Telomerase
Telomerase
in the ciliate Tetrahymena
Tetrahymena
was discovered by Carol W. Greider and Elizabeth Blackburn
Elizabeth Blackburn
in 1984.[5] Together with Jack W. Szostak, Greider and Blackburn were awarded the 2009 Nobel Prize
Nobel Prize
in Physiology or Medicine for their discovery.[6] The role of telomeres and telomerase in cell aging and cancer was established by scientists at biotechnology company Geron with the cloning of the RNA
RNA
and catalytic components of human telomerase[7] and the development of a polymerase chain reaction (PCR) based assay for telomerase activity called the TRAP assay, which surveys telomerase activity in multiple types of cancer.[8] Human telomerase structure[edit] The molecular composition of the human telomerase enzyme complex was determined by Dr Scott Cohen and his team at the Children's Medical Research Institute (Sydney Australia) and consists of two molecules each of human telomerase reverse transcriptase (TERT), telomerase RNA (TR or TERC), and dyskerin (DKC1).[9] The genes of telomerase subunits, which include TERT,[10] TERC,[11] DKC1[12] and TEP1,[13] are located on different chromosomes. The human TERT gene (hTERT) is translated into a protein of 1132 amino acids.[14] TERT polypeptide folds with (and carries) TERC, a non-coding RNA
RNA
(451 nucleotides long). TERT has a 'mitten' structure that allows it to wrap around the chromosome to add single-stranded telomere repeats. TERT is a reverse transcriptase, which is a class of enzyme that creates single-stranded DNA using single-stranded RNA
RNA
as a template.

An image illustrating how telomerase elongates telomere ends progressively.

The protein consists of four conserved domains (RNA-Binding Domain (TRBD), fingers, palm and thumb), organized into a ring configuration that shares common features with retroviral reverse transcriptases, viral RNA
RNA
polymerases and bacteriophage B-family DNA polymerases.[15][16] TERT proteins from many eukaryotes have been sequenced.[17] Mechanism[edit] By using TERC, TERT can add a six-nucleotide repeating sequence, 5'-TTAGGG (in 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'.[18] Telomerase
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. Telomerase
Telomerase
reverses telomere shortening. Clinical implications[edit] Aging[edit] Telomerase
Telomerase
replaces short bits of DNA known as telomeres, which are otherwise shortened when a cell divides via mitosis. In normal circumstances, absent telomerase, if a cell divides recursively, at some point the progeny reach their Hayflick limit,[19] which is believed to be between 50–70 cell divisions. At the limit the cells become senescent and cell division stops.[20] Telomerase allows each offspring to replace the lost bit of DNA allowing the cell line to divide without ever reaching the limit. This same unbounded growth is a feature of cancerous growth.[21] Embryonic stem cells
Embryonic stem cells
express telomerase, which allows them to divide repeatedly and form the individual. In adults, telomerase is highly expressed only in cells that need to divide regularly especially in male sperm cells[citation needed] but also in epidermal cells,[22] in activated T cell[23] and B cell[24] lymphocytes, as well as in certain adult stem cells, but in the great majority of cases somatic cells do not express telomerase.[25] A comparative biology study of mammalian telomeres indicated that telomere length of some mammalian species correlates inversely, rather than directly, with lifespan, and concluded that the contribution of telomere length to lifespan is unresolved.[26] Telomere
Telomere
shortening does not occur with age in some postmitotic tissues, such as in the rat brain.[27] In humans, skeletal muscle telomere lengths remain stable from ages 23 –74.[28] In baboon skeletal muscle, which consists of fully differentiated post-mitotic cells, less than 3% of myonuclei contain damaged telomeres and this percentage does not increase with age.[29] Thus, telomere shortening does not appear to be a major factor in the aging of the differentiated cells of brain or skeletal muscle. In human liver, cholangiocytes and hepatocytes show no age-related telomere shortening.[30] Another study found little evidence that, in humans, telomere length is a significant biomarker of normal aging with respect to important cognitive and physical abilities.[31] Some experiments have raised questions on whether telomerase can be used as an anti-aging therapy, namely, the fact that mice with elevated levels of telomerase have higher cancer incidence and hence do not live longer. Telomerase
Telomerase
also favors tumorogenesis, which leads to questions about its potential as an anti-aging therapy.[32] On the other hand, one study showed that activating telomerase in cancer-resistant mice by overexpressing its catalytic subunit extended lifespan.[33] Exposure of T lymphocytes
T lymphocytes
from HIV-infected human donors to a small molecule telomerase activator (TAT2) retards telomere shortening, increases proliferative potential and enhances cytokine/chemokine production and antiviral activity.[34] A study that focused on Ashkenazi Jews
Ashkenazi Jews
found that long-lived subjects inherited a hyperactive version of telomerase.[35] Mice engineered to block the gene that produces telomerase, unless they are given a certain drug, aged at a much faster rate, and died at about six months, instead of reaching the average mouse lifespan, about three years. Administering the drug at 6 months turned on telomerase production and caused their organs to be "rejuvenated," restored fertility, and normalized their ability to detect or process odors.[36][37] A 2012 study reported that introducing the TERT gene into healthy one-year-old mice using an engineered adeno-associated virus led to a 24% increase in lifespan, without any increase in cancer.[38] Premature aging[edit] Premature aging syndromes including Werner syndrome, Ataxia telangiectasia, Ataxia-telangiectasia like disorder, Bloom syndrome, Fanconi anemia
Fanconi anemia
and Nijmegen breakage syndrome
Nijmegen breakage syndrome
are associated with short telomeres.[39] However, the genes that have mutated in these diseases all have roles in the repair of DNA damage and the increased DNA damage may, itself, be a factor in the premature aging (see DNA damage theory of aging). An additional role in maintaining telomere length is an active area of investigation. Cancer[edit] In vitro, when cells approach the Hayflick limit, the time to senescence can be extended by inactivating the tumor suppressor proteins - p53 and Retinoblastoma protein
Retinoblastoma protein
(pRb).[citation needed] Cells that have been so-altered eventually undergo an event termed a "crisis" when the majority of the cells in the culture die. Sometimes, a cell does not stop dividing once it reaches crisis. In a typical situation, the telomeres are shortened[40] and chromosomal integrity declines with every subsequent cell division. Exposed chromosome ends are interpreted as double-stranded breaks (DSB) in DNA; such damage is usually repaired by reattaching (religating) the broken ends together. When the cell does this due to telomere-shortening, the ends of different chromosomes can be attached to each other. This solves the problem of lacking telomeres, but during cell division anaphase, the fused chromosomes are randomly ripped apart, causing many mutations and chromosomal abnormalities. As this process continues, the cell's genome becomes unstable. Eventually, either fatal damage is done to the cell's chromosomes (killing it via apoptosis), or an additional mutation that activates telomerase occurs.[citation needed] With telomerase activation some types of cells and their offspring become immortal (bypass the Hayflick limit), thus avoiding cell death as long as the conditions for their duplication are met. Many cancer cells are considered 'immortal' because telomerase activity allows them to live much longer than any other somatic cell, which, combined with uncontrollable cell proliferation[41] is why they can form tumors. A good example of immortal cancer cells is HeLa cells, which have been used in laboratories as a model cell line since 1951. While this method of modeling human cancer in cell culture is effective and has been used for many years by scientists, it is also very imprecise. The exact changes that allow for the formation of the tumorigenic clones in the above-described experiment are not clear. Scientists addressed this question by the serial introduction of multiple mutations present in a variety of human cancers. This has led to the identification of mutation combinations that form tumorigenic cells in a variety of cell types. While the combination varies by cell type, the following alterations are required in all cases: TERT activation, loss of p53 pathway function, loss of pRb pathway function, activation of the Ras or myc proto-oncogenes, and aberration of the PP2A protein phosphatase.[citation needed] That is to say, the cell has an activated telomerase, eliminating the process of death by chromosome instability or loss, absence of apoptosis-induction pathways, and continued mitosis activation. This model of cancer in cell culture accurately describes the role of telomerase in actual human tumors. Telomerase
Telomerase
activation has been observed in ~90% of all human tumors,[42] suggesting that the immortality conferred by telomerase plays a key role in cancer development. Of the tumors without TERT activation,[43] most employ a separate pathway to maintain telomere length termed Alternative Lengthening of Telomeres
Telomeres
(ALT ).[44] The exact mechanism behind telomere maintenance in the ALT pathway is unclear, but likely involves multiple recombination events at the telomere. Elizabeth Blackburn
Elizabeth Blackburn
et al., identified the upregulation of 70 genes known or suspected in cancer growth and spread through the body, and the activation of glycolysis, which enables cancer cells to rapidly use sugar to facilitate their programmed growth rate (roughly the growth rate of a fetus).[45] Approaches to controlling telomerase and telomeres for cancer therapy include gene therapy, immunotherapy, small-molecule and signal pathway inhibitors.[46] Drugs[edit] The ability to maintain functional telomeres may be one mechanism that allows cancer cells to grow in vitro for decades.[47] Telomerase activity is necessary to preserve many cancer types and is inactive in somatic cells, creating the possibility that telomerase inhibition could selectively repress cancer cell growth with minimal side effects.[48] If a drug can inhibit telomerase in cancer cells, the telomeres of successive generations will progressively shorten, limiting tumor growth.[49] Telomerase
Telomerase
is a good biomarker for cancer detection because most human cancers cells express high levels of it. Telomerase
Telomerase
activity can be identified by its catalytic protein domain (hTERT). This[clarify] is the rate-limiting step in telomerase activity. It is associated with many cancer types. Various cancer cells and fibroblasts transformed with hTERT cDNA have high telomerase activity, while somatic cells do not. Cells testing positive for hTERT have positive nuclear signals. Epithelial stem cell tissue and its early daughter cells are the only noncancerous cells in which hTERT can be detected. Since hTERT expression is dependent only on the number of tumor cells within a sample, the amount of hTERT indicates the severity of a cancer.[50] The expression of hTERT can also be used to distinguish benign tumors from malignant tumors. Malignant tumors
Malignant tumors
have higher hTERT expression than benign tumors. Real-time reverse transcription polymerase chain reaction (RT-PCR) quantifying hTERT expression in various tumor samples verified this varying expression.[51]

Figure 4:A) Tumor
Tumor
cells expressing hTERT will actively degrade some of the protein and process for presenting. The major histocompatibility complex 1(MHC1), can then present the hTERT epitote. CD8- T cells that have antibodies against hTERT will then bind to the presented epitote. B) As a result of the antigenic binding, the T cells will release cytotoxins, which can be absorbed by the affected cell. C) These cytotoxins induce multiple proteases and results in apoptosis (or cell death).

The lack of telomerase does not affect cell growth, until the telomeres are short enough to cause cells to “die or undergo growth arrest”. However, inhibiting telomerase alone is not enough to destroy large tumors. It must be combined with surgery, radiation, chemotherapy or immunotherapy.[50] Cells may reduce their telomere length by only 50-252 base pairs per cell division, which can lead to a long lag phase.[52][53] Immunotherapy[edit] Immunotherapy successfully treats some kinds of cancer, such as melanoma. This treatment involves manipulating a human’s immune system to destroy cancerous cells. Humans have two major antigen identifying lymphocytes: CD8+ cytotoxic T-lymphocytes (CTL) and CD4+ helper T-lymphocytes that can destroy cells. Antigen
Antigen
receptors on CTL can bind to a 9-10 amino acid chain that is presented by the major histocompatibility complex (MHC) as in Figure 4. HTERT
HTERT
is a potential target antigen. Immunotargeting should result in relatively few side effects since hTERT expression is associated only with telomerase and is not essential in almost all somatic cells.[54] GV1001 uses this pathway.[46] Experimental drug and vaccine therapies targeting active telomerase have been tested in mouse models, and clinical trials have begun. In 2014 Geron Corporation received permission to resume a trial of its drug imetelstat for myelofibrosis after addressing FDA concerns over liver toxicity.[55][56] Geron licensee Merck had approval of an IND for one vaccine type.[citation needed] Imetelstat (GRN163L) binds directly to the telomerase's RNA
RNA
template. One 2015 study reported that Imetelstat caused partial or complete remission in seven of 33 patients, while a second reported that it decreased blood platelet levels in all 18 study patients with essential thrombocythemia, a disorder in which the body overproduces blood platelets, increasing the risk of blood clots.[57] Most of the harmful cancer-related effects of telomerase are dependent on an intact RNA
RNA
template. Cancer
Cancer
stem cells that use an alternative method of telomere maintenance are still killed when telomerase's RNA template is blocked or damaged. Telomerase
Telomerase
Vaccines[edit] Two telomerase vaccines have been developed: GRNVAC1 and GV1001. GRNVAC1 isolates dendritic cells and the RNA
RNA
that codes for the telomerase protein and puts them back into the patient to make cytotoxic T cells that kill the telomerase-active cells. GV1001 is a peptide from the active site of hTERT and is recognized by the immune system that reacts by killing the telomerase-active cells.[46] Targeted apoptosis[edit]

Figure 5: A) Human telomerase RNA
RNA
(hTR) is present in the cell and can be targeted. B) 2-5 anti-hTR oligonucleotides is a specialized antisense oligo that can bind to the telomerase RNA. C) Once bound, the 2-5 anti-hTR oligonucleotide recruits RNase L to the sequence. Once recruited, the RNase L creates a single cleavage in the RNA
RNA
(D) and causes dissociation of the RNA
RNA
sequence.

Another independent approach is to use oligoadenylated anti-telomerase antisense oligonucleotides and ribozymes to target telomerase RNA, inducing dissociation and apoptosis (Figure 5). The fast induction of apoptosis through antisense binding may be a good alternative to the slower telomere shortening.[52] Small interfering RNA
RNA
(siRNA)[edit] siRNAs are small RNA
RNA
molecules that induce the sequence-specific degradation of other RNAs. si RNA
RNA
treatment can function similar to traditional gene therapy by destroying the m RNA
RNA
products of particular genes, and therefore preventing the expression of those genes. A 2012 study found that targeting TERC with an si RNA
RNA
reduced telomerase activity by more than 50% and resulted in decreased viability of immortal cancer cells.[58] Treatment with both the si RNA
RNA
and radiation caused a greater reduction in tumor size in mice than treatment with radiation alone, suggesting that targeting telomerase could be a way to increase the efficacy of radiation in treating radiation-resistant tumors. Heart disease, diabetes and quality of life[edit] Blackburn also discovered that mothers caring for very sick children have shorter telomeres when they report that their emotional stress is at a maximum and that telomerase was active at the site of blockages in coronary artery tissue, possibly accelerating heart attacks. In 2009, it was shown that the amount of telomerase activity significantly increased following psychological stress. Across the sample of patients telomerase activity in increased peripheral blood mononuclear cells by 18% one hour after the end of the stress.[59] E. V. Gostjeva et al. found no differences between colon cancer stem cells and fetal colon stem cells.[60] A study in 2010 found that there was "significantly greater" telomerase activity in participants than controls after a three-month meditation retreat.[61] Telomerase
Telomerase
deficiency has been linked to diabetes mellitus and impaired insulin secretion in mice, due to loss of pancreatic insulin-producing cells.[62] Rare human diseases[edit] Mutations in TERT have been implicated in predisposing patients to aplastic anemia, a disorder in which the bone marrow fails to produce blood cells, in 2005.[63] Cri du chat syndrome
Cri du chat syndrome
(CdCS) is a complex disorder involving the loss of the distal portion of the short arm of chromosome 5. TERT is located in the deleted region, and loss of one copy of TERT has been suggested as a cause or contributing factor of this disease.[64] Dyskeratosis congenita
Dyskeratosis congenita
(DC) is a disease of the bone marrow that can be caused by some mutations in the telomerase subunits.[65] In the DC cases, about 35% cases are X-linked-recessive on the DKC1 locus[66] and 5% cases are autosomal dominant on the TERT[67] and TERC[68] loci. Patients with DC have severe bone marrow failure manifesting as abnormal skin pigmentation, leucoplakia (a white thickening of the oral mucosa) and nail dystrophy, as well as a variety of other symptoms. Individuals with either TERC or DKC1 mutations have shorter telomeres and defective telomerase activity in vitro versus other individuals of the same age.[69] In one family autosomal dominant DC was linked to a heterozygous TERT mutation.[70] These patients also exhibited an increased rate of telomere-shortening, and genetic anticipation (i.e., the DC phenotype worsened with each generation). See also[edit]

DNA repair Imetelstat TA-65 Telomere

References[edit]

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Further reading[edit]

The Immortal Cell, by Michael D. West, Doubleday (2003) ISBN 978-0-385-50928-2

External links[edit]

The Telomerase
Telomerase
Database - A Web-based tool for telomerase research. Three-dimensional model of telomerase at MUN Elizabeth Blackburn's seminars: Telomeres
Telomeres
and Telomerase Telomerase
Telomerase
at the US National Library of Medicine Medical Subject Headings (MeSH)

v t e

DNA replication
DNA replication
(comparing Prokaryotic to Eukaryotic)

Initiation

Prokaryotic (initiation)

Pre-replication complex

dnaC

Cdc6

Helicase

dnaA dnaB T7

Primase

dnaG

Eukaryotic (preparation in G1 phase)

Pre-replication complex

Origin recognition complex

ORC1 ORC2 ORC3 ORC4 ORC5 ORC6

Cdc6

Cdt1

Minichromosome maintenance

MCM2 MCM3 MCM4 MCM5 MCM6 MCM7

Licensing factor

Autonomously replicating sequence

Single-strand binding protein

SSBP2 SSBP3 SSBP4

RNase H

RNASEH1 RNASEH2A

Helicase: HFM1

Primase: PRIM1 PRIM2

Both

Origin of replication/Ori/Replicon

Replication fork

Lagging and leading strands

Okazaki fragments Primer

Replication

Prokaryotic (elongation)

DNA polymerase
DNA polymerase
III holoenzyme

dnaC dnaE dnaH dnaN dnaQ dnaT dnaX holA holB holC holD holE

Replisome DNA ligase DNA clamp Topoisomerase

DNA gyrase

Prokaryotic DNA polymerase: DNA polymerase
DNA polymerase
I

Klenow fragment

Eukaryotic (synthesis in S phase)

Replication factor C

RFC1

Flap endonuclease

FEN1

Topoisomerase Replication protein A

RPA1

Eukaryotic DNA polymerase: alpha

POLA1 POLA2 PRIM1 PRIM2

delta

POLD1 POLD2 POLD3 POLD4

epsilon

POLE POLE2 POLE3 POLE4

DNA clamp

PCNA

Control of chromosome duplication

Both

Movement: Processivity DNA ligase

Termination

Telomere: Telomerase

TERT TERC DKC1

v t e

RNA-binding protein: Ribonucleoproteins

snRNP

A A1 B B2 C D1 D2 D3 E F G N

70K/U1 spliceosomal RNA

SNRNP200

hnRNP

A0 C L R

Other transcription

Telomerase

Translation

Ribosome

Vault ribonucleoprotein particles

Major vault protein

Other

Signal recognition particle

v t e

Transferases: phosphorus-containing groups (EC 2.7)

2.7.1-2.7.4: phosphotransferase/kinase (PO4)

2.7.1: OH acceptor

Hexo- Gluco- Fructo-

Hepatic

Galacto- Phosphofructo-

1 Liver Muscle Platelet 2

Riboflavin Shikimate Thymidine

ADP-thymidine

NAD+ Glycerol Pantothenate Mevalonate Pyruvate Deoxycytidine PFP Diacylglycerol Phosphoinositide 3

Class I PI 3 Class II PI 3

Sphingosine Glucose-1,6-bisphosphate synthase

2.7.2: COOH acceptor

Phosphoglycerate Aspartate kinase

2.7.3: N acceptor

Creatine

2.7.4: PO4 acceptor

Phosphomevalonate Adenylate Nucleoside-diphosphate Uridylate Guanylate Thiamine-diphosphate

2.7.6: diphosphotransferase (P2O7)

Ribose-phosphate diphosphokinase Thiamine diphosphokinase

2.7.7: nucleotidyltransferase (PO4-nucleoside)

Polymerase

DNA polymerase

DNA-directed DNA polymerase I II III IV V

RNA-directed DNA polymerase Reverse transcriptase

Telomerase

DNA nucleotidylexotransferase/Terminal deoxynucleotidyl transferase

RNA
RNA
nucleotidyltransferase

RNA
RNA
polymerase/DNA-directed RNA
RNA
polymerase RNA
RNA
polymerase I II III IV V Primase RNA-dependent RNA
RNA
polymerase

PNPase

Phosphorolytic 3' to 5' exoribonuclease

RNase PH PNPase

Nucleotidyltransferase

UTP—glucose-1-phosphate uridylyltransferase Galactose-1-phosphate uridylyltransferase

Guanylyltransferase

m RNA
RNA
capping enzyme

Other

Recombinase (Integrase) Transposase

2.7.8: miscellaneous

Phosphatidyltransferases

CDP-diacylglycerol—glycerol-3-phosphate 3-phosphatidyltransferase CDP-diacylglycerol—serine O-phosphatidyltransferase CDP-diacylglycerol—inositol 3-phosphatidyltransferase CDP-diacylglycerol—choline O-phosphatidyltransferase

Glycosyl-1-phosphotransferase

N-acetylglucosamine-1-phosphate transferase

2.7.10-2.7.13: protein kinase (PO4; protein acceptor)

2.7.10: protein-tyrosine

see tyrosine kinases

2.7.11: protein-serine/threonine

see serine/threonine-specific protein kinases

2.7.12: protein-dual-specificity

see serine/threonine-specific protein kinases

2.7.13: protein-histidine

Protein-histidine pros-kinase Protein-histidine tele-kinase Histidine kinase

v t e

Enzymes

Activity

Active site Binding site Catalytic triad Oxyanion hole Enzyme
Enzyme
promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme
Enzyme
catalysis

Regulation

Allosteric regulation Cooperativity Enzyme
Enzyme
inhibitor

Classification

EC number Enzyme
Enzyme
superfamily Enzyme
Enzyme
family List of enzymes

Kinetics

Enzyme
Enzyme
kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics

Types

EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list)

Molecular and Cellu

.