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Diving Into the World of Telomeres and Their Link to Disease

What are telomeres?


Human DNA is compacted into chromosomes to protect the important genetic material and to condense it enough to fit into the tiny nucleus of a cell. Telomeres are protective structures on the ends of chromosomes, which are made up of stretches of repetitive DNA sequences and proteins. They were first identified when researchers, Herman Muller and Barbara McClintock, were looking at the broken-ended chromosomes compared with normal ones. Muller discovered this by looking at irradiated Drosophila chromosomes (i.e. they had been exposed to radiation and so, had been damaged), whilst McClintock was researching corn genetics and found that rupture of the chromosomes could lead to fusion events. Chromosomes with broken ends were found to be unstable, whilst those with normal ends could prevent unwanted fusion events (between ends of broken chromosomes) and were more stable. This led to the definition of telomeres. Telomeres, therefore, protect the ends of chromosomes from being recognised as damaged DNA which would warrant incorrect repair.


Additionally, as a cell replicates, and so the DNA replicates, DNA polymerase will fail to replicate the entirety of the DNA, so some of the 3’ ends will be lost as the cell divides. This is known as ‘the end replication problem’, which occurs because DNA polymerase uses small RNA templates that do not allow for the whole 3’ end to be copied. Telomeres serve as non-coding pieces of DNA that are lost as the cell divides, meaning they do not produce proteins. This allows DNA that contains genes and the stability of the chromosome to be maintained, as the other parts of the chromosome are not lost.

Figure 1: The chromosome structure. Chromosomes are compacted structures of DNA, which are used to ensure the protection of genes and to make sure the genetic material will fit into the nucleus of the cell. They are made of two sister chromatids joined together at the centromere. Telomeres are present at the end of the short and long arms of chromosomes, in order to protect the organism’s genetic material that is contained within the chromosome.


Telomeric DNA is cytosine/guanine (C/G) rich, with the G-rich strand usually extending beyond the C-rich strand, producing a G-tail, this is shown in Figure 2. Very basic telomeric DNA includes sequences that are tandemly repeated, for example, TTAGGG in vertebrates (including humans); the length of which varies depending on the organism. Tandem repeats are repeated sequences that are directly adjacent (meaning "next to") to each other.


Reminder: Cytosine (C) and guanine (G) are complementary bases, which make up part of the genetic code along with thymine (T) and adenine (A). Cytosine and guanine have three hydrogen bonds between them, making them more difficult to separate than adenine and thymine, which have two hydrogen bonds between them. To read more about the structure of DNA, check out these Primer articles: A Brief Introduction to DNA and its History and An Overview of the Central Dogma of Molecular Biology.


Our DNA is subject to oxidative stress, in the form of reactive oxygen species, that damage the DNA, leading to telomere shortening as well. Reactive oxygen species are highly reactive molecules, for example, superoxide (O2.-). They may be produced in a variety of cellular processes, including during respiration and phagocytosis. However, they can also come from outside sources, such as tobacco smoke and pollutants.


As telomeres shorten and their DNA is lost, chromosomal instability increases, prompting the cell to enter either cellular senescence or cellular crisis. Cellular senescence describes the irreversible stopping of cell growth, whilst cellular crisis involves cell death. Senescence and crisis block tumour formation, defined as a group of aberrant cells that divide indefinitely.


Protection of telomeres


Telomeres serve essential functions, so their protection is important. Telomerase, so named because it is telomere-specific, is a reverse transcriptase, a type of enzyme that uses RNA as a template to produce DNA. This is a subunit known as TERT, which stands for telomerase reverse transcriptase. Telomerase also contains a short RNA, which it uses as a template to lengthen the ends of the telomeres. The RNA sequence will vary depending on the species. This RNA is known as TERC, for telomerase RNA component.


Other proteins associated with the TERC-TERT ribonucleoprotein (it is made of ribonucleic acid (RNA) and protein) complex, including the telomerase-associated protein 1 (TEP1) and some other proteins which aid binding of the telomerase to the telomeric DNA and recruitment of RNA molecules. These RNA molecules will be used to create the new telomeric DNA.


However, in humans, telomerase is only active in some cell types, including stem cells and cancer cells (discussed further below). These cells are not subject to cell division limits that are imposed upon most human cells. On one hand, the use of telomerase in cancer cells allows the tumour to grow indefinitely. On the other hand, this enzyme is important for stem cells to be able to constantly produce new cells as these replace dead or non-functional cells important for bodily function.


In addition, telomeric DNA is associated with protective proteins that maintain the integrity of the chromosomes. The shelterin complex, which protects human and other mammalian telomeres, is a six-protein complex. It contains telomere repeat factors 1 and 2 (TRF1 and TRF2) and protection of telomeres-1 (POT1), which directly bind telomeric DNA, RAP1, TRF1-interacting protein 2 (TIN2) and TPP1, which interact with TRF1, TRF2 and POT1. These six proteins are able to associate with other proteins, forming complex signalling networks to regulate telomere lengthening and protection.

Figure 2: The Shelterin complex. This simple diagram illustrates the binding of the shelterin complex binding to telomeric DNA, which is composed of hexameric (six nucleotides) repeats of TTAGGG. This diagram also shows the overhanging G-rich strand. Adapted from [de Lange, 2005].


Finally, telomeric DNA can form structures called T-loops, which provide additional protection against fusion events and incorrect DNA damage repair. Both TRF1 and TRF2 are involved in T-loop formation. This makes the DNA inaccessible to enzymes that mediate these events.

Figure 3: T-loops. Telomeric DNA forms a complex structure that provides an additional level of protection. Protein complexes (not shown) associate with various areas of the T-loop. Adapted from de Lange, (2004).

Figure 4: A diagram showing all the factors that contribute to telomere length regulation. Oxidative stress and incomplete DNA polymerase activity at the ends of chromosomes during cell division contribute to telomere shortening. On the other hand, telomerase, T-loops and the shelterin complex protect or lengthen telomeres.


What do telomeres have to do with ageing?


Ageing is characterised by the decline in health and function of cells and tissues, eventually leading to a decline in the function of the organism as a whole. As discussed before, telomeres in all dividing cells continue to shorten, inevitably limiting the lifespan of the cell, and ultimately ourselves, because our cells can only replicate so many times. For human fibroblasts, this is between 50-70 divisions. Fibroblasts are cells that produce the extracellular matrix, made up of different tissue types and molecules, which is present in between cells. When fibroblasts become senescent, they accumulate in different areas of the body, particularly the skin, contributing to ageing.


Additionally, shortened telomeres are also associated with conditions that have been found to shorten lifespan. For instance, there have been numerous studies showing how chronic stress causes loss of telomeric DNA.


This study compared the telomere length in mothers who had higher levels of chronic stress and those with lower levels. The group was split based on whether the mothers were carers of chronically ill children or not; those who were carers were determined to have higher levels of stress. They found that the mothers with greater chronic and perceived stress (i.e. the women who viewed the situation as stressful) had shorter telomeres. They also found that these women had more oxidative DNA damage and lower telomerase activity.


Shortened telomeres have been observed in patients with post-traumatic stress disorder (PTSD), major depression and other situations where the person experiences great amounts of psychological stress. Although more information is needed as to whether telomere length is directly affected by psychological stress, it is clear that stress reduces a person’s lifespan. Shorter telomeres have also been linked to exposure to a variety of carcinogens, including pollution from traffic, pesticides and lead.


Moreover, some people have genetic mutations that cause a rare disease called Dyskeratosis Congenita, leading to bone marrow failure and predispositions to cancer. These people have short telomeres in their germline cells (egg and sperm cells), meaning they experience a wide range of health issues, leading to premature ageing and death.


There are many other diseases that show more rapid and increased telomere shortening, such as HIV, Alzheimer’s and more.


So, surely to cure ageing, researchers would find a way to prevent telomere shortening, for example, by delivering telomerase to our cells?


Not quite!


Cancer cell immortality


During cancer formation, as a normal cell gains more and more mutations that make it malignant, these are known as the hallmarks of cancer. One of these is replicative immortality. This means cancer cells can divide over and over again, without any limitations, allowing rapid, uncontrollable growth of tumours. This is allowed, in the majority of cancers, by the presence of active telomerase, which counteracts the loss of telomeric DNA. Therefore, consistent telomere maintenance is not always beneficial.

Why should you care?


Telomere length is strongly linked to our health state; shortened telomeres are linked to conditions that resemble premature ageing and ageing itself. Telomeres present an interesting area of research to further understand how disease progression occurs, how we can diagnose disease and how we can prevent it. Greater understanding could also help to develop therapeutic strategies based on telomerase activation and telomere length maintenance.


On the other hand, abnormal telomere maintenance is present in many cancers, so, this may be something to consider when designing treatments for cancers as well.


Additionally, multiple studies have shown how reducing stress and other practices can counteract the telomere shortening that occurs due to psychological stress. For example, this study looked at how exercise affected telomere length. They found that individuals experiencing high levels of stress could counteract the effect that stress had on their telomere length by exercising. So, it may be worth considering how to decrease the perception of stress or bring some of these habits into our lives. Not to mention, there are also some studies that suggest antioxidants, which combat oxidative stress, could be useful to prevent telomere shortening.


In essence, this article just summarises telomeres and how fascinating they are. And if you are keen to learn more, do check out these links:

  • This is an invigorating TED Talk by Elizabeth Blackburn, who received the 2009 Nobel Prize in Physiology and Medicine (along with Carol Greider and Jack Szostak) for her discovery of telomerase:

  • This mini-game, called ‘Telomere Crisis’ was invented by Professor Phil Taylor (and Dr Kate Liddiard). Its primary aim is to demonstrate how shortened telomeres can cause a cell to become cancerous and proliferate uncontrollably:


Author


Ella Kline

BSc Biochemistry

Imperial College London


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