Telomerase
Encyclopedia
Telomerase is an enzyme
that adds DNA
sequence repeats ("TTAGGG" in all vertebrates) to the 3' end of DNA strands in the telomere
regions, which are found at the ends of eukaryotic
chromosomes. This region of repeated nucleotide
called telomeres contains non-coding DNA material and prevents constant loss of important DNA from chromosome ends. As a result, every time the chromosome is copied
only 100-200 nucleotides are lost, which causes no damage to the organism's DNA. Telomerase is a reverse transcriptase
that carries its own RNA
molecule, which is used as a template when it elongates telomeres, which are shortened after each replication cycle
.
The existence of a compensatory shortening of telomere (telomerase) mechanism was first predicted by Soviet biologist Alexey Olovnikov
in 1973, who also suggested the telomere hypothesis of aging and the telomere's connections to cancer. Telomerase was discovered by Carol W. Greider
and Elizabeth Blackburn
in 1984 in the ciliate Tetrahymena
. Together with Jack W. Szostak
, Greider and Blackburn were awarded the 2009 Nobel Prize
in Physiology or Medicine
for their discovery.
(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 nucleotide
s long in human). 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 as a template. Enzymes of this class (not TERT specifically, but the ones isolated from virus
es) are utilized by scientist
s in the molecular biological process of reverse transcriptase PCR
(RT-PCR), which allows the creation of several DNA copies of a target sequence using RNA as a template. As stated above, TERT carries its own template around, TERC.
The protein composition of human telomerase was identified in 2007 by Scott Cohen and his team at the Children's Medical Research Institute
in Australia. The high-resolution protein structure
of the Tribolium castaneum catalytic
subunit of telomerase TERT was decoded in 2008 by Emmanuel Skordalakes and his team at The Wistar Institute in Philadelphia. The structure revealed that the protein consists of four conserved domains (RNA-Binding Domain (TRBD), finger
s, palm and thumb
), organized into a ring configuration that shares common features with retroviral reverse transcriptases, viral RNA polymerase
s and bacteriophage
B-family DNA polymerases.
.
In normal circumstances, without the presence of telomerase, if a cell divides recursively, at some point all the progeny will reach their Hayflick limit
. With the presence of telomerase, each dividing cell can replace the lost bit of DNA, and any single cell can then divide unbounded. While this unbounded growth property has excited many researchers, caution is warranted in exploiting this property, as exactly this same unbounded growth is a crucial step in enabling cancerous growth
.
Embryonic stem cells express telomerase, which allows them to divide repeatedly and form the individual. In adults, telomerase is highly expressed in cells that need to divide regularly (e.g., in the immune system), whereas most somatic
cells express it only at very low levels in a cell-cycle-dependent manner.
A variety of premature aging syndromes are associated with short telomeres. These include Werner syndrome
, Ataxia telangiectasia
, Ataxia-telangiectasia like disorder, Bloom syndrome
, Fanconi anemia
, and Nijmegen breakage syndrome
. The genes that have been mutated in these diseases all have roles in the repair of DNA damage
, and their precise roles in maintaining telomere length are an active area of investigation. While it is currently unknown to what extent telomere erosion contributes to the normal aging process, maintenance of DNA in general and telomeric DNA, to be specific, have emerged as major players. Dr. Michael Fossel
has suggested in an interview that telomerase therapies may be used not only to combat cancer
but also to actually get around human aging and extend lifespan significantly. He believes human trials of telomerase-based therapies for extending lifespan will occur within the next 10 years. This timeline is significant because it coincides with the retirement of Baby Boomers in the United States
and Europe
.
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. In addition, certain premature aging syndromes have been associated with telomere shortening. Telomerase also favors tumorogenesis, leading to questions about its potential as an anti-aging therapy. On the other hand, one study showed that activating telomerase in cancer-resistant mice by overexpressing its catalytic subunit extended lifespan. The potential remains for telomerase activators to contribute to the development of cancer.
Exposure of T lymphocytes from HIV-infected human donors to a small molecule telomerase activator (TAT2) retards telomere shortening, increases proliferative potential, and, importantly, enhances cytokine/chemokine production and antiviral activity.
A study that focused on Ashkenazi Jews found that those that live the longest inherit a hyperactive version of telomerase that rebuilds telomeres.
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 of 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. The finding raises hope for treatment of conditions such as progeria
and other accelerated aging disorders, as well as possible organ regeneration therapies, such as repair of liver damage due to hepatitis or alcoholism.
A study published in the journal Nature in January 2011 found that Telomerase reactivation reversed tissue degeneration in older telomerase-deficient mice.
in cell culture
s, the time to senescence
can be extended by the inactivation of the tumor suppressor
proteins - TP53
and Retinoblastoma protein
(pRb). Cell
s that have been so-altered will 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 lost, and the integrity of the chromosomes 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 together. This temporarily solves the problem of lacking telomeres; but, during anaphase of cell division, the fused chromosomes are randomly ripped apart, causing many mutation
s and chromosomal abnormalities. As this process continues, the cell's genome becomes unstable. Eventually, either sufficient damage will be done to the cell's chromosomes such that cell dies (via programmed cell death, apoptosis
), or an additional mutation that activates telomerase will take place.
With the activation of telomerase, some types of cells and their offspring become immortal
, that is, their chromosomes will not become unstable no matter how many cell divisions they undergo (they bypass the Hayflick limit
), thus avoiding cell death as long as the conditions for their duplication are met. Many cancer cell
s are considered 'immortal' because telomerase activity allows them to divide virtually forever, which is why they can form tumor
s. A good example of cancer cells' immortality 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 clone
s in the above-described experiment are not clear. Scientists have subsequently been able to address this question by the serial introduction of several mutations present in a variety of human cancers. This has led to the elucidation of several combinations of mutations that are sufficient for the formation of tumorigenic cells, in a variety of cell types. While the combination varies depending on the cell type, a common theme is that the following alterations are required: activation of TERT, 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
. 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 activation of mitosis
.
This model of cancer
in cell culture accurately describes the role of telomerase in actual human tumors. Telomerase activation has been observed in ~90% of all human tumors, suggesting that the immortality conferred by telomerase plays a key role in cancer development. Of the tumors that have not activated TERT, most have found a separate pathway to maintain telomere length termed ALT (Alternative Lengthening of Telomeres). The exact mechanism behind telomere maintenance in the ALT pathway has not been elucidated, but likely involves multiple recombination events at the telomere.
et al., include the upregulation of 70 genes known or suspected in cancers' 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).
E. V. Gostjeva et al. (MIT) recently imaged colon cancer stem cells and compared them to fetal colon stem cells trying to make a new colon; they were the same.
Elizabeth Blackburn et al. UCSF has shown work that reveals that mothers caring for their very sick children have shorter telomeres when they report that their emotional stress is at the greatest point. She also found telomerase active at the site of blockages in coronary artery tissue. This could be why heart attacks can come on so suddenly: Telomerase is driving the growth of the blockage.
In 2009, it was shown that the amount of telomerase activity significantly increased due to psychological stress. Across the sample of patients telomerase activity increased by 18% one hour after the end of the stress. Telomerase activity was examined in peripheral blood mononuclear cells.
A study in 2010 found that there was, "significantly greater," telomerase activity in participants than controls after a three-month meditation retreat.
UC Davis Center for Mind and Brain, Davis, CA, USA
According to a 2007 study, there is no correlation between socio-economic status and telomere length.
Telomerase deficiency has been linked to diabetes mellitus and impaired insulin
secretion in mice, due to loss of insulin-producing cells in the pancreas.
Blackburn and the two other co-discoverers of telomerase won the Lasker Award
(2006), and the Nobel Prize
(2009) for the discovery of telomerase and subsequent work on telomerase. Blackburn also won the 2006 Gruber Genetics Prize for same.
, a disorder in which the bone marrow
fails to produce blood cells, in 2005.
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.
Dyskeratosis congenita
(DC) is a disease of the bone marrow
that can be caused by some mutations in the telomerase subunits. In the DC cases, about 35% cases are X-linked
-recessive on the DKC1 locus and 5% cases are autosomal
dominant on the TERT and TERC 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 than other individuals of the same age.
There has also been one family in which autosomal dominant DC has been linked to a heterozygous mutation in TERT. These patients also exhibited an increased rate of telomere-shortening, and genetic anticipation (i.e., the DC phenotype worsened with each generation).
target. If a drug can be used to turn off telomerase in cancer cells, the above process of telomere-shortening will resume—telomere length will be lost as the cells continue to divide, mutations will occur, and cell stability will decrease. Experimental drug and vaccine therapies targeting active telomerase have been tested in mouse models, and some have now entered early clinical trials. Geron Corporation is currently conducting four human clinical trials involving telomerase inhibition and telomerase vaccination. Merck, as a licensee of Geron, has recent approval of an IND for one vaccine type. The vaccine platform is being tested (and now jointly with Merck) using three different approaches. One vaccine is adenovirus/plasmid based (Merck IND). The second is an autologous dendritic cell based vaccine (GRNVAC1), formerly called TVAX when tested in Phase I clinical trials in Prostate Cancer, and it showed significant PSA doubling times as well as T-cell response. Geron's embryonic stem cell derived dendritic cell vaccine targeting telomerase is the third approach and is currently at the pre-clinical stage. These vaccine methods attempt to teach the human immune system to attack cancer cells expressing telomerase. Geron's telomerase inhibitor drug (GRN163L) attempts to stop cancer cell proliferation by inhibiting telomerase and it is in three separate early stage human clinical trials. Indeed, telomerase inhibition in many types of cancer cells grown in culture has led to the massive death of the cell population. However, a variety of caveats, including the presence of the ALT pathway, complicate such therapies. Some have reported ALT methods of telomere maintenance and storage of DNA in cancer stem cells, however Geron claims to have killed cancer stem cells with their telomerase inhibitor GRN163L at Johns Hopkins. GRN163L binds directly to the RNA template of telomerase. Even a mutation of the RNA template of telomerase would render the telomerase unable to extend telomeres, and therefore not be able to grant replicative immortality to cancer, not allow glycolysis to be inititated, and not upregulate Blackburn's 70 cancer genes. Since Blackburn has shown that most of the harmful cancer-related effects of telomerase are dependent on an intact RNA template, it seems a very worthwhile target for drug development. If indeed some cancer stem cells use an alternative method of telomere maintenance, it should be noted that they are still killed when the RNA template of telomerase is blocked. According to Blackburn's opinion at most of her lectures, it is a big mistake to think that telomerase is involved with only extending telomeres. Stopping glycolysis in cancer stem cells and preventing the upregulation of 70 bad genes is probably what is killing cancer stem cells if they are using alternative methods.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that adds DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
sequence repeats ("TTAGGG" in all vertebrates) to the 3' end of DNA strands in the telomere
Telomere
A telomere is a region of repetitive DNA sequences at the end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Its name is derived from the Greek nouns telos "end" and merοs "part"...
regions, which are found at the ends of eukaryotic
Eukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...
chromosomes. This region of repeated nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
called telomeres contains non-coding DNA material and prevents constant loss of important DNA from chromosome ends. As a result, every time the chromosome is copied
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
only 100-200 nucleotides are lost, which causes no damage to the organism's DNA. Telomerase is a reverse transcriptase
Reverse transcriptase
In the fields of molecular biology and biochemistry, a reverse transcriptase, also known as RNA-dependent DNA polymerase, is a DNA polymerase enzyme that transcribes single-stranded RNA into single-stranded DNA. It also helps in the formation of a double helix DNA once the RNA has been reverse...
that carries its own RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
molecule, which is used as a template when it elongates telomeres, which are shortened after each replication cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
.
The existence of a compensatory shortening of telomere (telomerase) mechanism was first predicted by Soviet biologist Alexey Olovnikov
Alexey Olovnikov
Alexey Matveyevich Olovnikov is a Russian biologist. In 1973, he was the first to recognize the problem of telomere shortening, to predict the existence of telomerase, and to suggest the telomere hypothesis of aging and the relationship of telomeres to cancer He was not awarded a share of the...
in 1973, who also suggested the telomere hypothesis of aging and the telomere's connections to cancer. Telomerase was discovered by Carol W. Greider
Carol W. Greider
Carolyn Widney "Carol" Greider is an American molecular biologist. She is Daniel Nathans Professor and Director of Molecular Biology and Genetics at Johns Hopkins University. She discovered the enzyme telomerase in 1984, when she was a graduate student of Elizabeth Blackburn at the University of...
and Elizabeth Blackburn
Elizabeth Blackburn
Elizabeth Helen Blackburn, AC, FRS is an Australian-born American biological researcher at the University of California, San Francisco, who studies the telomere, a structure at the end of chromosomes that protects the chromosome. Blackburn co-discovered telomerase, the enzyme that replenishes the...
in 1984 in the ciliate Tetrahymena
Tetrahymena
Tetrahymena are free-living ciliate protozoa that can also switch from commensalistic to pathogenic modes of survival. They are common in fresh-water. Tetrahymena species used as model organisms in biomedical research are T. thermophila and T. pyriformis.- T...
. Together with Jack W. Szostak
Jack W. Szostak
Jack William Szostak is a Canadian American biologist of Polish British descent and Professor of Genetics at Harvard Medical School and Alexander Rich Distinguished Investigator at Massachusetts General Hospital, Boston. He was awarded the 2009 Nobel Prize for Physiology or Medicine, along with...
, Greider and Blackburn were awarded the 2009 Nobel Prize
Nobel Prize
The Nobel Prizes are annual international awards bestowed by Scandinavian committees in recognition of cultural and scientific advances. The will of the Swedish chemist Alfred Nobel, the inventor of dynamite, established the prizes in 1895...
in Physiology or Medicine
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...
for their discovery.
Structure
Human telomerase consists of two molecules each of human telomerase reverse transcriptaseTelomerase reverse transcriptase
Telomerase reverse transcriptase is a catalytic subunit of the enzyme telomerase. Its absence is associated with the disorder Cri du chat....
(TERT), telomerase RNA
Telomerase RNA component
Telomerase RNA component, also known as TERC, is an RNA gene found in eukaryotes, that is a component of telomerase used to extend telomeres. Telomerase RNAs differ greatly in sequence and structure between vertebrates, ciliates and yeasts, but they share a 5' pseudoknot structure close to the...
(TR or TERC), and dyskerin
Dyskerin
H/ACA ribonucleoprotein complex subunit 4 is a protein that in humans is encoded by the DKC1 gene.-External links:*...
(DKC1). The genes of telomerase subunits, which are TERT, TERC, DKC1, and TEP1 etc, are located on different chromosomes in the human genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
. Human TERT gene (hTERT) is translated
Translation (genetics)
In molecular biology and genetics, translation is the third stage of protein biosynthesis . In translation, messenger RNA produced by transcription is decoded by the ribosome to produce a specific amino acid chain, or polypeptide, that will later fold into an active protein...
into a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
of 1132 amino acids. TERT proteins from many eukaryotes have been sequenced. TERT polypeptide folds
Protein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
with TERC, a non-coding RNA
Non-coding RNA
A non-coding RNA is a functional RNA molecule that is not translated into a protein. Less-frequently used synonyms are non-protein-coding RNA , non-messenger RNA and functional RNA . The term small RNA is often used for short bacterial ncRNAs...
(451 nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
s long in human). TERT has a 'mitten' structure that allows it to wrap around the chromosome to add single-stranded telomere repeats.
TERT is a reverse transcriptase
Reverse transcriptase
In the fields of molecular biology and biochemistry, a reverse transcriptase, also known as RNA-dependent DNA polymerase, is a DNA polymerase enzyme that transcribes single-stranded RNA into single-stranded DNA. It also helps in the formation of a double helix DNA once the RNA has been reverse...
, which is a class of enzyme that creates single-stranded DNA using single-stranded RNA as a template. Enzymes of this class (not TERT specifically, but the ones isolated from virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
es) are utilized by scientist
Scientist
A scientist in a broad sense is one engaging in a systematic activity to acquire knowledge. In a more restricted sense, a scientist is an individual who uses the scientific method. The person may be an expert in one or more areas of science. This article focuses on the more restricted use of the word...
s in the molecular biological process of reverse transcriptase PCR
Reverse transcription polymerase chain reaction
Reverse transcription polymerase chain reaction is a variant of polymerase chain reaction , a laboratory technique commonly used in molecular biology to generate many copies of a DNA sequence, a process termed "amplification"...
(RT-PCR), which allows the creation of several DNA copies of a target sequence using RNA as a template. As stated above, TERT carries its own template around, TERC.
The protein composition of human telomerase was identified in 2007 by Scott Cohen and his team at the Children's Medical Research Institute
Children's Medical Research Institute
The Children's Medical Research Institute is an Australian based independent scientific research organisation created in the 1950s by Paediatricians Sir Lorimer Dods and Dr. John Fulton to "perform scientific research with a commitment to better treat, and where possible, prevent childhood...
in Australia. The high-resolution protein structure
Protein structure
Proteins are an important class of biological macromolecules present in all organisms. Proteins are polymers of amino acids. Classified by their physical size, proteins are nanoparticles . Each protein polymer – also known as a polypeptide – consists of a sequence formed from 20 possible L-α-amino...
of the Tribolium castaneum catalytic
Catalysis
Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....
subunit of telomerase TERT was decoded in 2008 by Emmanuel Skordalakes and his team at The Wistar Institute in Philadelphia. The structure revealed that the protein consists of four conserved domains (RNA-Binding Domain (TRBD), finger
Finger
A finger is a limb of the human body and a type of digit, an organ of manipulation and sensation found in the hands of humans and other primates....
s, palm and thumb
Thumb
The thumb is the first digit of the hand. When a person is standing in the medical anatomical position , the thumb is the lateral-most digit...
), organized into a ring configuration that shares common features with retroviral reverse transcriptases, viral RNA polymerase
Polymerase
A polymerase is an enzyme whose central function is associated with polymers of nucleic acids such as RNA and DNA.The primary function of a polymerase is the polymerization of new DNA or RNA against an existing DNA or RNA template in the processes of replication and transcription...
s and bacteriophage
Bacteriophage
A bacteriophage is any one of a number of viruses that infect bacteria. They do this by injecting genetic material, which they carry enclosed in an outer protein capsid...
B-family DNA polymerases.
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'. 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.)Aging
The enzyme telomerase allows for replacement of short bits of DNA known as telomeres, which are otherwise shortened when a cell divides via mitosisMitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
.
In normal circumstances, without the presence of telomerase, if a cell divides recursively, at some point all the progeny will reach their Hayflick limit
Hayflick limit
The Hayflick limit is the number of times a normal cell population will divide before it stops, presumably because the telomeres reach a critical length....
. With the presence of telomerase, each dividing cell can replace the lost bit of DNA, and any single cell can then divide unbounded. While this unbounded growth property has excited many researchers, caution is warranted in exploiting this property, as exactly this same unbounded growth is a crucial step in enabling cancerous growth
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
.
Embryonic stem cells express telomerase, which allows them to divide repeatedly and form the individual. In adults, telomerase is highly expressed in cells that need to divide regularly (e.g., in the immune system), whereas most somatic
Somatic
The term somatic means 'of the body',, relating to the body. In medicine, somatic illness is bodily, not mental, illness. The term is often used in biology to refer to the cells of the body in contrast to the germ line cells which usually give rise to the gametes...
cells express it only at very low levels in a cell-cycle-dependent manner.
A variety of premature aging syndromes are associated with short telomeres. These include Werner syndrome
Werner syndrome
Werner syndrome is a very rare, autosomal recessive disorder characterized by the appearance of premature aging....
, Ataxia telangiectasia
Ataxia telangiectasia
Ataxia telangiectasia is a rare, neurodegenerative, inherited disease that affects many parts of the body and causes severe disability. Ataxia refers to poor coordination and telangiectasia to small dilated blood vessels, both of which are hallmarks of the disease...
, Ataxia-telangiectasia like disorder, Bloom syndrome
Bloom syndrome
Bloom's syndrome , also known as Bloom–Torre–Machacek syndrome, is a rare autosomal recessive chromosomal disorder characterized by a high frequency of breaks and rearrangements in an affected person's chromosomes. The condition was discovered and first described by dermatologist Dr...
, Fanconi anemia
Fanconi anemia
Fanconi anemia is a genetic disease with an incidence of 1 per 350,000 births, with a higher frequency in Ashkenazi Jews and Afrikaners in South Africa.FA is the result of a genetic defect in a cluster of proteins responsible for DNA repair...
, and Nijmegen breakage syndrome
Nijmegen breakage syndrome
Nijmegen breakage syndrome , also known as Berlin breakage syndrome and Seemanova syndrome, is a rare autosomal recessive congenital disorder causing chromosomal instability, probably as a result of a defect in the Double Holliday junction DNA repair mechanism.NBS1 codes for a protein that has two...
. The genes that have been mutated in these diseases all have roles in the repair of DNA damage
DNA repair
DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
, and their precise roles in maintaining telomere length are an active area of investigation. While it is currently unknown to what extent telomere erosion contributes to the normal aging process, maintenance of DNA in general and telomeric DNA, to be specific, have emerged as major players. Dr. Michael Fossel
Michael Fossel
Michael B. Fossel, M.D., Ph.D. is a professor of clinical medicine at Michigan State University and editor of the Journal Of Anti-Ageing Medicine who is best known for his views on telomerase therapy as a possible treatment for cellular senescence...
has suggested in an interview that telomerase therapies may be used not only to combat cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
but also to actually get around human aging and extend lifespan significantly. He believes human trials of telomerase-based therapies for extending lifespan will occur within the next 10 years. This timeline is significant because it coincides with the retirement of Baby Boomers in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
and Europe
Europe
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...
.
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. In addition, certain premature aging syndromes have been associated with telomere shortening. Telomerase also favors tumorogenesis, leading to questions about its potential as an anti-aging therapy. On the other hand, one study showed that activating telomerase in cancer-resistant mice by overexpressing its catalytic subunit extended lifespan. The potential remains for telomerase activators to contribute to the development of cancer.
Exposure of T lymphocytes from HIV-infected human donors to a small molecule telomerase activator (TAT2) retards telomere shortening, increases proliferative potential, and, importantly, enhances cytokine/chemokine production and antiviral activity.
A study that focused on Ashkenazi Jews found that those that live the longest inherit a hyperactive version of telomerase that rebuilds telomeres.
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 of 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. The finding raises hope for treatment of conditions such as progeria
Progeria
Progeria is an extremely rare genetic condition wherein symptoms resembling aspects of aging are manifested at an early age. The word progeria comes from the Greek words "pro" , meaning "before", and "géras" , meaning "old age"...
and other accelerated aging disorders, as well as possible organ regeneration therapies, such as repair of liver damage due to hepatitis or alcoholism.
A study published in the journal Nature in January 2011 found that Telomerase reactivation reversed tissue degeneration in older telomerase-deficient mice.
Cancer
When cells are approaching the Hayflick limitHayflick limit
The Hayflick limit is the number of times a normal cell population will divide before it stops, presumably because the telomeres reach a critical length....
in cell culture
Cell culture
Cell culture is the complex process by which cells are grown under controlled conditions. In practice, the term "cell culture" has come to refer to the culturing of cells derived from singlecellular eukaryotes, especially animal cells. However, there are also cultures of plants, fungi and microbes,...
s, the time to senescence
Senescence
Senescence or biological aging is the change in the biology of an organism as it ages after its maturity. Such changes range from those affecting its cells and their function to those affecting the whole organism...
can be extended by the inactivation of the tumor suppressor
Tumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
proteins - TP53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
and Retinoblastoma protein
Retinoblastoma protein
The retinoblastoma protein is a tumor suppressor protein that is dysfunctional in the majority types of cancer. One highly studied function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide...
(pRb). Cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
s that have been so-altered will 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 lost, and the integrity of the chromosomes declines with every subsequent cell division. Exposed chromosome ends are interpreted as double-stranded breaks (DSB) in DNA; such damage is usually repaired
DNA repair
DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
by reattaching (religating) the broken ends together. When the cell does this due to telomere-shortening, the ends of different chromosomes can be attached together. This temporarily solves the problem of lacking telomeres; but, during anaphase of cell division, the fused chromosomes are randomly ripped apart, causing many mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s and chromosomal abnormalities. As this process continues, the cell's genome becomes unstable. Eventually, either sufficient damage will be done to the cell's chromosomes such that cell dies (via programmed cell death, apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
), or an additional mutation that activates telomerase will take place.
With the activation of telomerase, some types of cells and their offspring become immortal
Biological immortality
Biological immortality refers to a stable rate of mortality as a function of chronological age. Some individual cells and entire organisms in some species achieve this state either throughout their existence or after living long enough. This requires that death occur from injury or disease rather...
, that is, their chromosomes will not become unstable no matter how many cell divisions they undergo (they bypass the Hayflick limit
Hayflick limit
The Hayflick limit is the number of times a normal cell population will divide before it stops, presumably because the telomeres reach a critical length....
), thus avoiding cell death as long as the conditions for their duplication are met. Many cancer cell
Cancer cell
Cancer cells are cells that grow and divide at an unregulated, quickened pace. Although cancer cells can be quite common in a person they are only malignant when the other cells fail to recognize and/or destroy them. In the past a common belief was that cancer cells failed to be recognized and...
s are considered 'immortal' because telomerase activity allows them to divide virtually forever, which is why they can form tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
s. A good example of cancer cells' immortality 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 clone
Cloning
Cloning in biology is the process of producing similar populations of genetically identical individuals that occurs in nature when organisms such as bacteria, insects or plants reproduce asexually. Cloning in biotechnology refers to processes used to create copies of DNA fragments , cells , or...
s in the above-described experiment are not clear. Scientists have subsequently been able to address this question by the serial introduction of several mutations present in a variety of human cancers. This has led to the elucidation of several combinations of mutations that are sufficient for the formation of tumorigenic cells, in a variety of cell types. While the combination varies depending on the cell type, a common theme is that the following alterations are required: activation of TERT, 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
Phosphatase
A phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group . This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their...
. 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 activation of mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
.
This model of cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
in cell culture accurately describes the role of telomerase in actual human tumors. Telomerase activation has been observed in ~90% of all human tumors, suggesting that the immortality conferred by telomerase plays a key role in cancer development. Of the tumors that have not activated TERT, most have found a separate pathway to maintain telomere length termed ALT (Alternative Lengthening of Telomeres). The exact mechanism behind telomere maintenance in the ALT pathway has not been elucidated, but likely involves multiple recombination events at the telomere.
Additional roles in cancer, heart disease, diabetes and quality of life
Additional roles for telomerase per work by Elizabeth BlackburnElizabeth Blackburn
Elizabeth Helen Blackburn, AC, FRS is an Australian-born American biological researcher at the University of California, San Francisco, who studies the telomere, a structure at the end of chromosomes that protects the chromosome. Blackburn co-discovered telomerase, the enzyme that replenishes the...
et al., include the upregulation of 70 genes known or suspected in cancers' 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).
E. V. Gostjeva et al. (MIT) recently imaged colon cancer stem cells and compared them to fetal colon stem cells trying to make a new colon; they were the same.
Elizabeth Blackburn et al. UCSF has shown work that reveals that mothers caring for their very sick children have shorter telomeres when they report that their emotional stress is at the greatest point. She also found telomerase active at the site of blockages in coronary artery tissue. This could be why heart attacks can come on so suddenly: Telomerase is driving the growth of the blockage.
In 2009, it was shown that the amount of telomerase activity significantly increased due to psychological stress. Across the sample of patients telomerase activity increased by 18% one hour after the end of the stress. Telomerase activity was examined in peripheral blood mononuclear cells.
A study in 2010 found that there was, "significantly greater," telomerase activity in participants than controls after a three-month meditation retreat.
UC Davis Center for Mind and Brain, Davis, CA, USA
According to a 2007 study, there is no correlation between socio-economic status and telomere length.
Telomerase deficiency has been linked to diabetes mellitus and impaired insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
secretion in mice, due to loss of insulin-producing cells in the pancreas.
Blackburn and the two other co-discoverers of telomerase won the Lasker Award
Lasker Award
The Lasker Awards have been awarded annually since 1946 to living persons who have made major contributions to medical science or who have performed public service on behalf of medicine. They are administered by the Lasker Foundation, founded by advertising pioneer Albert Lasker and his wife Mary...
(2006), and the Nobel Prize
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...
(2009) for the discovery of telomerase and subsequent work on telomerase. Blackburn also won the 2006 Gruber Genetics Prize for same.
Role in other human diseases
Mutations in TERT have been implicated in predisposing patients to aplastic anemiaAplastic anemia
Aplastic anemia is a condition where bone marrow does not produce sufficient new cells to replenish blood cells. The condition, per its name, involves both aplasia and anemia...
, a disorder in which the bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
fails to produce blood cells, in 2005.
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.
Dyskeratosis congenita
Dyskeratosis congenita
Dyskeratosis congenita , also called Zinsser-Cole-Engman syndrome, is a rare progressive congenital disorder which results in what in some ways resembles premature aging...
(DC) is a disease of the bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
that can be caused by some mutations in the telomerase subunits. In the DC cases, about 35% cases are X-linked
Sex linkage
Sex linkage is the phenotypic expression of an allele related to the chromosomal sex of the individual. This mode of inheritance is in contrast to the inheritance of traits on autosomal chromosomes, where both sexes have the same probability of inheritance...
-recessive on the DKC1 locus and 5% cases are autosomal
Autosome
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
dominant on the TERT and TERC 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 than other individuals of the same age.
There has also been one family in which autosomal dominant DC has been linked to a heterozygous mutation in TERT. These patients also exhibited an increased rate of telomere-shortening, and genetic anticipation (i.e., the DC phenotype worsened with each generation).
Telomerase as a potential drug target
Cancer is a very difficult disease to fight because the immune system has trouble recognizing it. Because telomerase is necessary for the immortality of so many cancer types, it is thought to be a potential drugDrug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
target. If a drug can be used to turn off telomerase in cancer cells, the above process of telomere-shortening will resume—telomere length will be lost as the cells continue to divide, mutations will occur, and cell stability will decrease. Experimental drug and vaccine therapies targeting active telomerase have been tested in mouse models, and some have now entered early clinical trials. Geron Corporation is currently conducting four human clinical trials involving telomerase inhibition and telomerase vaccination. Merck, as a licensee of Geron, has recent approval of an IND for one vaccine type. The vaccine platform is being tested (and now jointly with Merck) using three different approaches. One vaccine is adenovirus/plasmid based (Merck IND). The second is an autologous dendritic cell based vaccine (GRNVAC1), formerly called TVAX when tested in Phase I clinical trials in Prostate Cancer, and it showed significant PSA doubling times as well as T-cell response. Geron's embryonic stem cell derived dendritic cell vaccine targeting telomerase is the third approach and is currently at the pre-clinical stage. These vaccine methods attempt to teach the human immune system to attack cancer cells expressing telomerase. Geron's telomerase inhibitor drug (GRN163L) attempts to stop cancer cell proliferation by inhibiting telomerase and it is in three separate early stage human clinical trials. Indeed, telomerase inhibition in many types of cancer cells grown in culture has led to the massive death of the cell population. However, a variety of caveats, including the presence of the ALT pathway, complicate such therapies. Some have reported ALT methods of telomere maintenance and storage of DNA in cancer stem cells, however Geron claims to have killed cancer stem cells with their telomerase inhibitor GRN163L at Johns Hopkins. GRN163L binds directly to the RNA template of telomerase. Even a mutation of the RNA template of telomerase would render the telomerase unable to extend telomeres, and therefore not be able to grant replicative immortality to cancer, not allow glycolysis to be inititated, and not upregulate Blackburn's 70 cancer genes. Since Blackburn has shown that most of the harmful cancer-related effects of telomerase are dependent on an intact RNA template, it seems a very worthwhile target for drug development. If indeed some cancer stem cells use an alternative method of telomere maintenance, it should be noted that they are still killed when the RNA template of telomerase is blocked. According to Blackburn's opinion at most of her lectures, it is a big mistake to think that telomerase is involved with only extending telomeres. Stopping glycolysis in cancer stem cells and preventing the upregulation of 70 bad genes is probably what is killing cancer stem cells if they are using alternative methods.
External links
- T.A. Sciences live Q&A Event on Telomere Video on Demand event
- The Telomerase Database - A Web-based tool for telomerase research.
- Three-dimensional model of telomerase at MUNMemorial University of NewfoundlandMemorial University of Newfoundland, is a comprehensive university located primarily in St...
- Telomeres and Telomerase: Their Implications in Human Health and Disease on-line lecture by Elizabeth BlackburnElizabeth BlackburnElizabeth Helen Blackburn, AC, FRS is an Australian-born American biological researcher at the University of California, San Francisco, who studies the telomere, a structure at the end of chromosomes that protects the chromosome. Blackburn co-discovered telomerase, the enzyme that replenishes the...
