Telomeres are short stretches of DNA that exist at the ends of chromosomes in cells. In 2009, Dr. Elizabeth Blackburn won the Nobel Prize in Physiology or Medicine for her outstanding contributions to telomere research. Telomeres are like the plastic bundles at the end of shoelaces, which can maintain the integrity of chromosomes and control the cell division cycle. They can also be called the protectors of chromosomes.
Telomeres may be linked to biology of cancer and aging
A team at the University of North Carolina ( UNC ) has discovered that DNA repeats, once thought to be too simple and monotonous, cannot encode proteins. But telomeres contain the genetic information to produce two dipeptide repeat proteins, one of which is elevated in some human cancer cells, as well as in cells from patients with telomere-related defects.The research team published this article in < Proceedings of the National Academy of Science, PNAS >titled “Mammalian telomeric RNA”, the article pointed out that a simple blood test for these proteins can provide valuable information for some cancers and other human diseases, plus telomeres will change with time. Shortening with age, these tests can also measure the health of telomeres.
About 80 years ago, scientists identified telomeres, the ends of chromosomes. In mammals and many other organisms, it contains a unique DNA sequence consisting of multiple repeats of TTAGGG bases that inhibits chromosomes from sticking to each other. As cells divide, telomeres shorten, eventually becoming so short that cells can no longer divide normally, resulting in cell death. About 20 years ago, Griffith’s group’s lab showed that the ends of telomeric DNA loop back on themselves, forming a small circle that hides the ends and prevents chromosome-to-chromosome fusion. In eukaryotes, telomeres are transcribed and produce G-rich RNA (G-rich RNA), called TERRA. Scientists in related fields believe that telomeres cannot encode proteins, let alone have biological functions, due to their monotonous repetitive sequences. As Griffith and Al-Turki point out in their newly published work: “This RNA has long been thought to be purely structural and not to code for protein.”
ALS-associated RNA bears striking similarity to telomere RNA
Interestingly, in 2011, a team in Florida who studied ALS (Amyotrophic Lateral Sclerosis, ALS) reported that the culprit of ALS was an RNA molecule containing a hexabase repeat sequence , by a mechanism that produces a series of toxic proteins consisting of two amino acids. “Recently found in several human nucleotide expansion disorders, RNA transcripts containing long repeats can form secondary structures that can be translated in multiple frames to produce isopeptides or bispeptides,” the UNC researchers explained. peptide repeat proteins, which have been shown in multiple studies to be toxic to cells.”
The research team noticed that the ALS-associated RNA was very similar to that produced by telomeres and hypothesized that the same mechanism might exist. In several human diseases, the repeat-associated non-ATG translation mechanism (RAN), if used by mammalian TERRA, may generate two dipeptide repeat proteins: repeat valine-arginine ( valine–arginine, VR ) and repeated glycine-leucine ( glycine–leucine, GL ). Other scientists performed experiments on their reported research to demonstrate that this telomeric DNA could direct cells to produce two dipeptide repeat proteins, and found that they could indeed act as signaling proteins, triggering a chain reaction of other proteins in the cell.
Telomere DNA can act as a signaling protein, triggering a chain reaction of other proteins
Then, Al-Turki and Griffith chemically synthesized VR and GL, generated polyclonal antibodies against repeat VR dipeptide proteins, and examined the properties of these two proteins using advanced biological methods. Their results show that the VR protein is elevated in certain human cancer cells, as well as in cells from patients with diseases caused by defective telomeres. According to the research team, when cells undergo a telomere crisis, repetitive dipeptide proteins are produced in large quantities, which may alter nucleic acid metabolism and general protein synthesis, and trigger an inflammatory response in cells.
Griffith further pointed out: “When you challenge current perceptions, you are usually wrong, because you are opposing many people who are working hard in their fields. But sometimes scientists fail to combine observations from two very distant fields. Putting it all together, here’s what we did. The discovery that telomeres encode two new types of signaling proteins will change our understanding of cancer, aging, and how cells communicate with other cells. Many questions remain to be answered, but the first priority is to provide Develop a simple blood test that can tell our body’s biological age, or provide warnings of problems such as cancer or inflammation. And until more is known about these double-peptide repeat proteins, their unique biological activity should not be assumed related to toxicity.” There are many issues that require further research in the future, such as the study of the synthesis, degradation and levels of VR and GL dipeptide proteins in the cell cycle, and the general analysis of their toxicity, understanding their function in the cell important clues.
Further reading: Junk gene regulation of telomerase double-edged sword? Anti-aging but good for cancer cell proliferation?
References:
1. https://www.pnas.org/doi/10.1073/pnas.2221529120
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