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Telomeres and telomerase

Telomeres as protective "caps" on the tips of eukaryotic chromosomes. How telomerase extends telomeres.

Introduction

If you could zoom in and look at the DNA on the tip of one of your chromosomes, what would you see? You might expect to find genes, or perhaps some DNA sequences involved in gene regulation. Instead, what you'd actually find is a single sequence –TTAGGG – repeated over and over again, hundreds or even thousands of times.
Telomeres appear as the bright spots at the ends of each chromosome in the picture shown above. Image credit: "Telomere caps," by U.S. Department of Energy Human Genome Program (public domain).
Repetitive regions at the very ends of chromosomes are called telomeres, and they're found in a wide range of eukaryotic species, from human beings to unicellular protists. Telomeres act as caps that protect the internal regions of the chromosomes, and they're worn down a small amount in each round of DNA replication.
In this article, we'll take a closer look at why telomeres are needed, why they shorten during DNA replication, and how the enzyme telomerase can be used to extend them.

The end-replication problem

Unlike bacterial chromosomes, the chromosomes of eukaryotes are linear (rod-shaped), meaning that they have ends. These ends pose a problem for DNA replication. The DNA at the very end of the chromosome cannot be fully copied in each round of replication, resulting in a slow, gradual shortening of the chromosome.
Why is this the case? When DNA is being copied, one of the two new strands of DNA at a replication fork is made continuously and is called the leading strand. The other strand is produced in many small pieces called Okazaki fragments, each of which begins with its own RNA primer, and is known as the lagging strand. (See the article on DNA replication for more details.)
In most cases, the primers of the Okazaki fragments can be easily replaced with DNA and the fragments connected to form an unbroken strand. When the replication fork reaches the end of the chromosome, however, there is (in many species, including humans) a short stretch of DNA that does not get covered by an Okazaki fragment—essentially, there's no way to get the fragment started because the primer would fall beyond the chromosome endstart superscript, 1, end superscript. Also, the primer of the last Okazaki fragment that does get made can't be replaced with DNA like other primers.
Thanks to these problems, part of the DNA at the end of a eukaryotic chromosome goes uncopied in each round of replication, leaving a single-stranded overhang. Over multiple rounds of cell division, the chromosome will get shorter and shorter as this process repeats.
A real eukaryotic chromosome would have multiple origins of replication and multiple replication bubbles, but the end-replication problem would be the same as shown above. Image modified from "Telomere shortening," by Zlir'a, public domain.
In human cells, the last RNA primer of the lagging strand may be positioned as much as 70 to 100 nucleotides away from the chromosome endsquared. Thus, the single-stranded overhangs produced by incomplete end replication in humans are fairly long, and the chromosome shortens significantly with each round of cell division.

Telomeres

To prevent the loss of genes as chromosome ends wear down, the tips of eukaryotic chromosomes have specialized DNA “caps” called telomeres. Telomeres consist of hundreds or thousands of repeats of the same short DNA sequence, which varies between organisms but is 5'-TTAGGG-3' in humans and other mammals.
Telomeres need to be protected from a cell's DNA repair systems because they have single-stranded overhangs, which "look like" damaged DNA. The overhang at the lagging strand end of the chromosome is due to incomplete end replication (see figure above). The overhang at the leading strand end of the chromosome is actually generated by enzymes that cut away part of the DNAstart superscript, 1, end superscript.
In some species (including humans), the single-stranded overhangs bind to complementary repeats in the nearby double-stranded DNA, causing the telomere ends to form protective loopscubed. Proteins associated with the telomere ends also help protect them and prevent them from triggering DNA repair pathways.
Image credit: "Telomere," by Samulili (CC BY-SA 3.0).
The repeats that make up a telomere are eaten away slowly over many division cycles, providing a buffer that protects the internal chromosome regions bearing the genes (at least, for some period of time). Telomere shortening has been connected to the aging of cells, and the progressive loss of telomeres may explain why cells can only divide a certain number of timesstart superscript, 4, end superscript.

Telomerase

Some cells have the ability to reverse telomere shortening by expressing telomerase, an enzyme that extends the telomeres of chromosomes. Telomerase is an RNA-dependent DNA polymerase, meaning an enzyme that can make DNA using RNA as a template.
How does telomerase work? The enzyme binds to a special RNA molecule that contains a sequence complementary to the telomeric repeat. It extends (adds nucleotides to) the overhanging strand of the telomere DNA using this complementary RNA as a template. When the overhang is long enough, a matching strand can be made by the normal DNA replication machinery (that is, using an RNA primer and DNA polymerase), producing double-stranded DNA.
The primer may not be positioned right at the chromosome end and cannot be replaced with DNA, so an overhang will still be present. However, the overall length of the telomere will be greater.
_Image modified from "Working principle of telomerase," by Fatma Uzbas (CC BY-SA 3.0). The modified image is licensed under a CC BY-SA 3.0 license._
Telomerase is not usually active in most somatic cells (cells of the body), but it’s active in germ cells (the cells that make sperm and eggs) and some adult stem cells. These are cell types that need to undergo many divisions, or, in the case of germ cells, give rise to a new organism with its telomeric “clock” resetstart superscript, 5, end superscript.
Interestingly, many cancer cells have shortened telomeres, and telomerase is active in these cells. If telomerase could be inhibited by drugs as part of cancer therapy, their excess division (and thus, the growth of the cancerous tumor) could potentially be stopped.

Want to join the conversation?

  • piceratops ultimate style avatar for user ryan.oswald
    A question I've had for a while is how are telomeres and the sections of DNA that they protect not worn our through the duration of human existence or life in general? Although the number of divisions from zygote to producing gametes may not be "many" in terms of cellular divisions, it seems to me that the damage should add up over time. Does anyone have an answer?
    (12 votes)
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  • blobby green style avatar for user Chen Yuxin
    Since most somatic cells do not have the telomerase, I wonder how they will deal with the overhang?? Will the overhang just stay there? Or bein removed somehow??
    (2 votes)
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    • blobby green style avatar for user MatejTymes
      This most probably is not true, as telomeres are actually a prevention mechanism from things like cancer. When our cells divide the original dna is mutated while copied. Most of these mutations are gradually damaging the function of the cell. After certain amount of division the dna is so damaged that the cell doesn't function normally and a cancer cell is born (Imagine the game "chinese whispers" played with dna). Most of these damaged cells die out naturally, but sometimes it happens that the telomere mechanism is broken and the cancer cells starts replicating even when it normally shouldn't anymore and forms a tumor (this is why cancer lines we extracted from dead people and use in labs are immortal - because the telomere mechanism is damaged while human cells aren't). So no "doping" telomerase to make human immortal most possibly would not work (which is kind of sad).
      (3 votes)
  • leaf yellow style avatar for user pace.myrna
    I don't quite fully understand why the leading strand doesn't have telomeres? After all, they too have primers that must be substituted with DNA?
    (5 votes)
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  • blobby green style avatar for user shane.kim8796
    I'm having trouble understanding the telomere's protective loop, which is also referred to as a T-loop structure with G-quadruplex. After each cell division(mitosis), telomere sequences become gradually shortened. I'm wondering what happens to this protective loop structure. Are they reformed or rearranged with the what is left of the telomere sequence in new DNA copies or does the newly copied DNA exist in a linear form without a loop? As far as my understand goes, this loop has a 3' end overhang at the end which forms G-quadruplex(also called tetrad G) and I don't see how this happens in mitosis in which telomerase is not activated with telomere sequences getting curtailed. Also, tetrad G structure can't really be formed by the DNA polymerase (right?). I would really appreciate your answer.
    (4 votes)
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  • blobby green style avatar for user rosaroos99
    Is DNA polymerase using Telomerase's RNA template as primer? Or is the primer made by primase?
    (3 votes)
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    • blobby green style avatar for user Alcantara
      RNA primers in DNA replication are laid down onto the leading and lagging strands by an enzyme called primase. RNA primers are made up of DNA and they signal where DNA polymerase III needs to start adding DNA nucleotides also known as DNA bases (in order for DNA copying to start). The RNA primers are removed by another enzyme called DNA polymerase I.
      (1 vote)
  • piceratops ultimate style avatar for user john bruner
    if telomerase can initiate a protective loop inhibiting the end of DNA damage then why is it inactive in most cells?
    (2 votes)
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  • blobby green style avatar for user sharkas99
    "The end-replication problem..... essentially, there's no way to get the fragment started because the primer would fall beyond the chromosome end."

    why is this the case? is there a specific distance a new primer needs from its preceding primer to be built?
    (2 votes)
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  • leaf green style avatar for user Mahasish Shome
    When does telomerase starts to elongate telomere? I mean how short (in base pairs) does the telomere need to be in order to activate telomerase?
    (2 votes)
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  • blobby green style avatar for user saifulislamrmc888
    If there is no change at the extended 3' overhang then this end will be longer in each replication.Does it really be longer gradually?
    (2 votes)
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  • aqualine seedling style avatar for user charlize.stein
    Are there telomeres on both the leading and lagging strand of DNA?
    (2 votes)
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