HomeENGLISH MAGAZINETelomere hALTing in disease: facing their "shortcoming" is pivotal for aging cells...

Telomere hALTing in disease: facing their “shortcoming” is pivotal for aging cells to loose TERRAin

A new study led by researchers at Instituto de Medicina Molecular João Lobo Antunes- iMM and published today in the prestigious journal Proceedings of the National Academy of Sciences (PNAS) shows, for the first time, that the cell’s anti-aging structures – the telomeres – can set the damage threshold a cancer cell can sustain and above which cells cannot continue to divide and die. These results open new possibilities for cancer therapeutics and other common and lethal diseases. Telomeres protect the ends of our chromosomes, much like the plastic cap at the end of a shoelace that prevents the lace from unravelling. Over a cell’s lifetime, telomeres get gradually shorter with each cell division and therefore the protective cap becomes less and less effective. If they get too short, it is a signal for the cell that its genetic material is compromised and the cell stops dividing. Telomere shortening and reduced cell division are considered a hallmark of ageing and likely contribute to the ageing process.

Telomere shortening is a double-edged sword and has to be carefully regulated to strike a balance between ageing and cancer prevention. When a telomere accidentally gets cut short early in a cell’s lifetime, it needs to be fixed so that the cell doesn’t become senescent too early. Therefore, telomere shortening is also a defense mechanism against cancer, like a cell aging clock, because highly proliferative cells can only divide when their telomeres do not shorten. The majority of cancer cells are able to stop this aging clock through the action of telomerase, a molecule that counteracts the shortening of chromosome ends. But approximately 10% of the human tumors are made of a type of cancer cells – ALT cells – that are able to maintain their telomeres without the action of telomerase and are particularly resistant to conventional chemotherapies. ALT cells are able to keep controlled levels of DNA damage in their telomeres at each cell division, and this feature is required for their telomeres to divide indefinitely.

Now, Bruno Silva and Claus M. Azzalin at iMM have discovered that the source of this damage is TERRA, an RNA molecule produced from the telomeres, that accumulates specifically at the ends of critically short telomeres by binding directly to the DNA and signals to the cell that these telomeres should be repaired, allowing the cell to carry on dividing. Previously, scientists discovered that this molecule has an important role in this process of damaging the DNA and its stability and abundance is regualted by an helicase called RTEL1. Now, they figured out what molecular mechanism happens inside these ALT cells. When 5 years ago they went looking into the regulation of TERRA in the cell cycle and found that TERRA levels were different at different stages of the cell cycle. When they discovered that the pattern of cyclic TERRA accumulation was different between short and long telomeres, they delved more and realized that TERRA actually accumulates at all telomeres, but at long telomeres it is rapidly removed with the help of proteins RAT1 and RNase H2.

These proteins bind preferentially to the long telomeres and ensure that TERRA is removed, but they are not present at the critically short telomeres, which means that TERRA remains for a longer time. This mechanism ensures the subsequent repair of the short telomere, which is crucial for the cell to survive and keep dividing.While in normal cells, TERRA is only present at very low levels and its physiological function is still largely unknown, in ALT cells TERRA molecules are naturally more abundant. However, when the research team used molecular tools to further increase the levels of TERRA inside the ALT cancer cells, they observed accumulation of damage in the DNA of the telomeres. This manipulation has two outputs for the ALT cancer cell: first, the maintenance of the damaged telomere is activated and second, to restore this damage, other telomeres are used and lost. The consequence for the cancer cell is catastrophic: it cannot stand onto multiple damaged telomeres and stops dividing.

These exciting results open a new window for the development of therapeutic protocols for treatment of ALT cancers. But tumors are not the only medical condition that would benefit from expanding this knowledge. A condition in which the pathological shortening of telomeres occurs is chronic heart failure (CHF). During recent years, several reports suggested a connection between telomere dysfunction and cardiovascular pathology. Oxidative stress has also been suggested to be a modulator of telomere loss and reactive oxygen specie production in failing heart cells are either mediator and further trigger of tissue damage and progression of the disease. A study published in 2017 officially discovered, for the first time, that post‐mitotic cardiomyocytes from CHF patients have significantly shorter telomeres compared with healthy individuals. Scientists also found that the observed telomere shortening occurs in a cell type‐specific manner.

Further, in‐depth analysis revealed that cardiomyocytes with the shortest telomeric lengths are mainly from patients with reduced ejection fraction. It has been, indeed, recently reported elevated oxidative stress, potentially exacerbated by oxidative DNA damage, in cardiac tissues that exhibit short telomeres. These findings are in accordance with previous reports suggesting oxidative stress as a contributor to telomere shortening independent of cell replication. The hypothesis that telomere shortening happens in cardiomyocytes within failing animal and human hearts is not new; it started almost 20 years ago and only in the last 5-6 years there have been accumulating evidence that telomere shortening in human hearts could be considered an hallmark of CHF. Along with the increased knowledge of telomere biology and associated proteins (TIN2, TEL1, TRF2, POT-2, FANC proteins, etc.), there is also the possibility to engineer molecules to modulate these complex molecular patterns.

It has, for example, very recently published a research about small modulators of the TERRA molecule mentioned earlier (the structures picted here). Specifically, three lead chromene derivatives have been shown to interfere with TERRA RNA, telomerase and arranged DNA structures called G-quadruplex. These compounds have snown selectivity and antiproliferative potential in some cellular models like HT-29 (colon cancer), MCF7 (breast cancer) and A549 (lung cancer) and may represent a totally new avenue of treating cancer. On the contrary, a way to allow a recovery of some telomeric lenght would be appropriate for the halting of the heart failure progression. A classical PI3K/c-Akt pathway activated by growth factors like PDGF, BDNF and others, is able to promote the activity of cellular telomerase and the telomere mainteinance; yet, a direct approach with this primary mechanism for failing heart cells has not been achieved with practical means.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Silva B et al. Proc Natl Acad Sci USA 2022 Sep; 119(39).

Bhargava R et al. DNA Repair (Amst). 2022; 115:103342.

Rocca R et al. Pharmaceuticals (Basel) 2022; 15(5):548.

Silva B, Arora R et al. Nat Commun. 2021; 12(1):3760.

Ghisays F, Garzia A et a. Nat Commun. 2021; 12(1):3016.

Adishesh M et al. Int J Mol Sci. 2020 Nov; 21(22):8686.

Pan X, Chen Y et al. Sci Rep. 2019 Dec 13; 9(1):19110.

Quryshi N et al. Int J Mol Sci. 2018 Mar 10; 19(3):797.

Sharifi SM et al. J Am Heart Assoc. 2017; 6(9):e005086.

Chang AC et al. PNAS USA 2016; 113(46):13120-13125.

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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