Telomere

A chromosome (left) and a telomer (to the right).

The telomeres (from the Greek τέλος [telos], «end», and μέρος [meros], «part») are the ends of chromosomes. They are highly repetitive, non-coding DNA regions whose main function is the structural stability of chromosomes in eukaryotic cells, cell division and the lifespan of cell lines. They are also involved in diseases as important as cancer.

Prokaryotic organisms have circular chromosomes that do not have telomeres. Some prokaryotes possess linear chromosomes with telomeric sequences, the sequence of which is different from that of eukaryotes.

Discovery of telomeres

In the early 1970s, Russian theorist Alexei Olovnikov first recognized that chromosomes could not fully replicate their ends. Building on this, and to accommodate Leonard Hayflick's idea of limited somatic cell division, Olovnikov suggested that DNA sequences are lost each time a cell replicates until the loss reaches a critical level, at which point division ends. cell phone.

Scientists Elizabeth H. Blackburn, Carol W. Greider, and Jack W. Szostak are awarded the 2009 Nobel Prize in medicine for the molecular description of telomeres, the demonstration of their evolutionary conservation, and the discovery of telomerase, central enzyme of the cellular machinery for telomere synthesis, for having achieved a very consistent model that explains the 'replication termination problem' (end-replication problem) and the molecular mechanism of protection of chromosome ends.

In 1983, Barbara McClintock received the Nobel Prize. Since then, she has come a long way in understanding telomeres, thanks to molecular genetics techniques. They proposed that the telomeres, located at the ends of the chromosomes, had the function of preventing them from fusing when they came into contact at their ends, which would produce disastrous consequences for the cells.

General considerations

In the chromosomes there are two types of DNA: the coding DNA, which constitutes the genes, that is, portions of the chromosome where the information that encodes the proteins is found, the transfer ribonucleic acid and the ribosomal ribonucleic acids, scattered between a large amount of non-coding DNA. Non-coding DNA includes that which forms the centromere and telomeres of chromosomes. The centromere is an elongated portion of DNA that allows the DNA molecule to attach to the mitotic spindle during the M phase of the cell cycle. For their part, telomeres play an important role in the life of cells since they maintain the integrity of the ends of the chromosomes, preventing them from becoming entangled and adhering to each other, helping homologous chromosomes to pair up and cross over during prophase. of meiosis. Human and mouse telomeres^{[citation needed]} contain up to 2000 times the 5' TTAGGG 3':

5'...TTAGGG TTAGGGG TTAGGGG TTAGGGG TTAGGGGGGGG..3'
3'...AATCCC AATCCC AATCCC AATCCC AATCCC AATCCC.5'

Aging and carcinogenesis

Some theories of aging and carcinogenesis are based on the fact that telomeres are like clocks or timers in the cell, since they mark the number of cell divisions, until the cell dies. The foundations of these theories are:

• The DNA contained in the telomers is not completely replicated during DNA duplication, as polymerase DNA enzymes can only work in direction 5'-give3'. For one of the two strands (conductor) this does not pose a problem, but in order to simultaneously duplicate the delayed strand (which is presented in direction 3'-/20055') the Okazaki fragments must be formed. The beginning of each segment is made up of a first RNA. These are finally replaced by DNA, however, the first of the end 5' of the strand cannot be completed, as it would be required to work towards 3'-105'. As a result, the telomer that is becoming more and shorter in each replication.
• Telomers, in most animal and plant species and in microorganisms, are made up of short subunits of nucleotides usually rich in thymine (T) and guanine (G). In humans the sequence of each of these subunits is TTAGGG.
• The number of repetitions is variable according to the different cells of the same individual; however the average repetitions is usually constant for each species. In one person it is estimated that it reaches about 2000 repetitions. According to Consulosky Slater.^{[chuckles]required]}
• Telomerase is an enzyme formed by a protein-acid ribonucleic complex with inverse transcripatase activity (i.e., it can synthesize DNA from a sequence of RNA that it itself carries), which is produced in embryonic germ cells that allows the spread of the telomers.
• Telomerase is repressed in mature somatic cells after birth, which produces a shortening of the telomer after each cell division.
• When the length of the telomer reaches a certain limit, the mitosis is interrupted by remaining cells in the G0 (G Zero) stage of your cell cycle.
• The wear of the telomer in the course of cell cycles prevents its protective function of chromosome, thus becoming unstable, merges or is lost. The cells that present these defects are not only incapable of duplicating, but are no longer viable and the processes of apoptosis or programmed cell death are activated.
• Many cancer cells reactivate the activity of telomerase, favoring the proliferation of an evil clone. Drugs that inhibit telomerase are being studied and thus stop the growth of malignant cells, so it could be a new therapeutic target of cancer^{[chuckles]required]}.

Specialists from the National Cancer Research Center (CNIO) have developed a treatment that acts on genes that, applied once in adult animals, safely extends the average life of individuals. This type of investigation forced to permanently modify the genes of the animals from the embryonic phase. However, the gene therapy developed by the CNIO to combat aging has been tested in adult mice aged one and two years, and had a "rejuvenating" effect on them.

The procedure consists of trying to modify the genetic load of a virus whose DNA has been modified; their genes are replaced by one of the most important genes for aging in the treated species: the one that encodes the telomerase enzyme. Telomerase stops this effect, rebuilds telomeres and corrects the cell's biological clock. The virus with the treated DNA and inoculated into the animal acts as a vehicle that deposits the telomerase gene in the cells.

The replication of linear chromosomes poses a problem

DNA polymerase can only make new DNA strands when it moves along the template strand, polymerizing nucleotides in the 5' direction. → 3' (on a pattern strand of polarity 3' → 5'). This does not pose a problem for the thread named "continuous" of a chromosome, since the polymerase can move freely and uninterruptedly from the origin of replication to the end of the chromosome or until it encounters a termination signal. The same does not happen when the template strand is the one with directionality 5´ → 3' whose replication must necessarily be discontinuous, since the replication complex moves in coordination on the two parental strands, with opposite directions. When the replication fork has opened sufficiently, DNA polymerase synthesizes a fragment of complementary DNA in the opposite direction to the advance of the replication complex. After this fragment is formed, the synthesis of a new primer initiates the polymerization of a new fragment, and so on. Later, these pieces of DNA (called Okazaki fragments) will be spliced together using a ligase.

However, upon reaching the end of the chromosome, the last Okazaki fragment is at a distance from the end of its template strand that is insufficient for the addition of a new primer. For this reason, the discontinuous chain cannot be completed and asymmetric shortening (ie, only in the daughter strand) of the telomere occurs. During each replication, the process repeats itself, progressively shortening the telomeres at both ends of the chromosome. It is estimated that human cells lose about 100 base pairs of telomeric DNA with each replication. This represents about 16 TTAGGG fragments. Taking into account the initial number of these sequences, after about 125 mitotic divisions, the telomere has been completely lost.

The question is: is it because of this that in somatic cells, after a certain number of divisions, the cell dies?

Hayflick's experiments showed that normal (non-cancerous) cells do not grow in vitro indefinitely despite being supplied with all the necessary nutrients and growth factors. Cells obtained from newborns cultured in vitro undergo about 100 divisions, while cells obtained from older subjects only divide 20 to 24 times. Is this due to telomeres representing like a clock that determines the longevity of cells? cells?

In favor of this hypothesis is the fact that some cells are immortal, such as germ cells, unicellular eukaryotic cells (such as Paramecium) or some tumor cells. In all of them there is an enzyme called telomerase that after each division restores the integrity of the telomeres.

Telomerase (TERT)

Telomerase is a reverse transcriptase that synthesizes DNA from an RNA template. It is a ribonucleoprotein that contains in its molecule the AAUCCC sequence capable of creating and inserting the TTAGGG fragments that are lost in each division. In 1998, Bodnar et al introduced into two types of normal, telomerase-negative human cells, the gene encoding telomerase. In contrast to normal cells that showed senescence and shortened telomeres, TERT-expressing clones showed elongated telomeres, divided vigorously, and showed reduced beta-galactosidase, a biomarker of senescence. Cells transformed to express TERT showed a normal karyotype and their longevity has exceeded normal by more than 20 divisions.

Many cancer cells are derived from somatic cells, and the presence of telomerase has been found in 75-80% of tumor lines. This is not to say that telomerase induces cancer. Furthermore, Kathleen Collins of the University of California at Berkeley,^{[citation needed]} found that patients with a very rare congenital disease, dyskeratosis congenita, had telomerase levels abnormally low, yet dying in many cases of gastrointestinal cancer. Despite this inconsistency, it is known that the aggressiveness of tumor cells is related to their telomerase levels and that high levels of this enzyme are indicative of tumor malignancy. The FDA has recently authorized two clinical studies with telomerase, one of them aimed at obtaining a better diagnosis of cervical cancer and the other to evaluate a drug against myeloid leukemia.^{[citation needed]}

In Japan it is being used in children with 4S neuroblastoma. These children appear to have metastatic cancer, but the tumors are telomerase negative and approximately 80% go into spontaneous remission once the tumor has been surgically removed. The study identifies those who are telomerase-positive so that they can be treated more aggressively.

Some known telomere sequences

Quotes