What are telomeres?

A telomere is a region of repetitive nucleotide sequences appearing at each end of a chromosome. Telomeres are typical of eukaryotic cells, which have linear chromosomes, but most prokaryotes, such as bacteria, have circular chromosomes and no telomeres.

The word telomere comes from the Greek τέλος [telos] (end), and μέρος [meros] (part). They were discovered in 1933 by Barbara McClintock when observing that the chromosomes that did not have the final part clumped together.

McClintock suggested the existence of a special sequence or structure at chromosome ends responsible for chromosome stability. Later, in 1983, McClintock would receive the Nobel Prize in Physiology or Medicine for his work on genetic rearrangement.

Telomere Structure

The DNA (deoxyribonucleic acid) molecule consists of a sequence of nucleotides. Each nucleotide is a molecule made up of a type of carbohydrate. pentose (5 carbon atoms), one nitrogen base and a Phosphate group (H3PO4).

In DNA the pentose is deoxyribose, in RNA it is ribose. Nitrogenous bases can be purine bases (adenine and guanine), or pyrimidine bases (thiamin and cytosine in DNA, cytosine and uracil in RNA). A genetic sequence is designated by the initials of the nitrogenous base of the nucleotides that form the sequence. For example, AGTTCAT etc.

Each human chromosome is made up of a linear chain of thousands or millions of nucleotides. At each end of this chain appears a repetitive nucleotide sequence which are known as telomeres.

Telomeres, in addition to being highly repetitive sequences, are sequences highly conserved throughout evolution, which makes them the same in large groups of living organisms. The telomeres of humans and other vertebrates consist mainly of the repetition of a very simple sequence, the sequence TTAGGG.

The telomere length It is highly variable between different species. It can range from 300 base pairs in yeast to several tens of kilobases in humans. Telomeres usually end in single strands of DNA coiled into what are called T loops (T loops), which stabilize and close the telomere.

In T-loops, a protein complex called shelterin or telosoma that protects telomeres and regulates the action of telomerasean enzyme capable of lengthening telomeres.

Most prokaryotic organisms have circular chromosomes that do not have telomeres. However, some bacteria with linear chromosomes are known, for example, species of Streptomyces, AgrobacteriumY borrelia (causing borreliosis or Lyme disease), which also have telomeres, although with a different structure from eukaryotic telomeres.

Telomere function

During eukaryotic cell division, its DNA has to replicate, the cell has to make a copy of its genome for the new cells. The most important enzyme in replication is DNA polymerase. This enzyme cannot completely replicate the chromatin fibers to the end, so end sequences are lost in each new cell generation.

Terminal telomeres are sequences of non-coding DNA that protects the chromosomes preventing the loss of information from affecting genes and other coding sequences. telomeres act as protective caps for chromosomes.

To replace the telomeres that are lost, the cells have telomerase, an enzyme that catalyzes the formation and addition of the telomeric sequence to the chromosomes.

Unfortunately, in most multicellular eukaryotic organisms, including humans, telomerase is only active in germ cellsthe cells that give rise to eggs and sperm.

In the rest of the cells (somatic cells), there is a progressive shortening of telomeres until it reaches a critical level prevents the cell from dividing. This limited capacity for cell division seems to be closely related to the agingbecause the body loses the ability to regenerate.

shortening of telomeres

Telomere shortening is largely due to DNA replication problem showing eukaryotic cells and, in general, all cells with linear chromosomes. DNA replication does not start at one end and end at the other end, but rather begins in the middle, at a place known as the origin of replication.

Based on the orientation of the nucleotides, one end of a DNA strand is called the 3' and the other 5'. From the origin of replication, the DNA polymerase enzyme reads the strand that acts as the template in direction 3′ → 5′ continuously and is synthesizing a new copy. The copy will be complementary strand with opposite orientation, the copy grows in the 5′ → 3′ direction.

But when the replication complex separates the two strands that make up the DNA helix, one strand is in the correct reading orientation (3' → 5') and the other is in the opposite direction (5' → 3'). Unlike before, the replication of this last strand is produced discontinuouslysince the replication complex moves in a coordinated manner anchored to the two DNA strands and can only read in the 3' → 5' direction and synthesize in the complementary direction.

In this way, a strand of DNA called conductive or continuous threadand a thread called lagging thread.

Lagging strand synthesis uses RNA fragments known as RNA primer, initiator, primer or RNA "primer". The RNA primer is positioned at a forward position relative to the replication complex, and the replication complex can bind at these positions to the RNA primer and fall back to synthesize the replicated lagging-strand DNA fragment. This is how they are created RNA primer fragments and replicated DNA known as okazaki shards.

Okazaki fragments are linked together by the action of the enzyme DNA ligase. The RNA primer fragments are replaced by replicated DNA from the complementary strand in front of them. And this is where the problem of replication of eukaryotic cells arises: the RNA primer at the end will not have complementary DNA to replicate and replace.

That Residual primer RNA is destroyed by enzymatic action and, consequently, part of the telomeres is lost in each cell division. Each generation of cells will present shorter telomeres at the 5′ end of the lagging strand.

Telomere shortening, stress and health

Numerous experiments and studies have shown a significant difference between the expected telomere shortening at each cell division and the actual shortening that occurs. And it is that numerous factors seem to influence the shortening of telomeres, and not only the structural and enzymatic factors of the genetic replication mechanism.

The oxidative stress and DNA damage caused by free radicals causes telomere shortening greater than that caused by replication problems.

Some population studies have shown a certain relationship between the intake of antioxidant nutrients, such as vitamin C, E and beta-carotene, and the length of telomeres. The lower the amount of antioxidants, the greater the shortening of telomeres.

All these factors could increase the risk of some types of cancer, for example breast cancer (Long Island Breast Cancer Study Project), and degenerative diseases, in addition to their effect on aging and longevity.

Although it has also been related psychological stress and anxiety with accelerated telomere shortening, there are also studies showing a very low correlation between perceived psychological stress and the length of the telomeres, although among the doubts raised by these experiments is the real difficulty in measuring psychological stress.

Elongation

The telomere lengthening is carried out naturally by the enzyme telomerase, which has been synthesized and is the subject of intense studies. The action of telomerase has already shown in the laboratory that it is capable of extend cell lifewhich could be used in the future to extend life or slow down aging.

Although no lengthening method has yet been tested in humans, possible mechanisms of telomerase activation include pharmacological, genetic, and metabolic treatments.

In mice, it has been possible to see how the lengthening of telomeres, or more precisely the activation of telomerase, reverses some signs of aging.

However, a complete understanding of telomeres and their function seems to be a long way off. For example, mammalian species have been discovered whose longevity and life expectancy are related to telomere length in an inverse proportional way, which leaves open the controversy between aging, longevity and telomere length.

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