In a recent study published in PNAS, researchers have discovered for the first time that telomeres can produce proteins. Not only does this challenge our previous understanding of telomeres, but it could provide a new biomarker for biological age and issues such as cancer or inflammation.
What are telomeres?
Telomeres are structures found at the ends of chromosomes, consisting of long arrays of short nucleotide repeats. Their main function is to protect chromosomes from fusing end-to-end, which would be catastrophic for the cell. Telomeres block end-to-end fusions through end-loop formation, or t-loop, which are maintained by specific telomere-associated proteins like TRF1 and TRF2.
Although telomeres were discovered in the late 1930s, new research is revealing that they are not merely repetitive DNA sequences. In fact, they have surprising functions, one of which was thought to be impossible – that is, until now. Due to their simplicity, scientists previously thought that telomeres could not produce proteins. But in this latest study, the team of researchers from Penn State College of Medicine show that telomeres can produce 2 signalling proteins called VR (valine-arginine) and GL (glycine-leucine).
So how do they produce these proteins?
In mammals, telomeres are transcribed from subtelomeric promoters by RNA polymerase II, producing a long G-rich RNA (UUAGGG)n termed TERRA. TERRA plays a crucial role in maintaining the structure of telomeres. As a long (previously thought to be non-coding) RNA molecule, TERRA binds to telomeric DNA and participates in the formation of higher-order telomere structures such as the t-loop, which helps to prevent the chromosome ends from being recognized as DNA damage and facilitates telomere protection. Additionally, TERRA has been shown to interact with telomere-associated proteins such as TRF1 and TRF2, and can modulate their function, further contributing to the regulation of telomere structure and function.
Ribosomes are able to load and begin translation at hairpins or G-quadruplexes through repeat associated non-ATG translation (RAN), generating a series of dipeptide repeat proteins. The RAN mechanism has previously been implicated in several human diseases such as ALS. The researchers behind this study hypothesised that, if utilized by mammalian TERRA, RAN translation could generate two dipeptide repeat proteins – repeating valine–arginine and repeating glycine–leucine. And they were right – this study is the first to demonstrate that the G-rich RNA transcript TERRA encodes these two repeating dipeptide proteins.
What are GL and VR?
Proteins GL and VR have been found to contribute to the formation of amyloid, which can activate the innate immune response and trigger general inflammatory responses in the body. Both GL and VR have the ability to form filaments and amyloid-like structures, with VR exhibiting strong nucleic acid binding properties. Moreover, recent research indicates that telomeres generate both telomere-specific RNA and biologically active microproteins, including GL and VR. High levels of these microproteins could lead to altered RNA and ribosome biogenesis and nucleic acid metabolism, resulting in toxicity that may indicate dysfunctional or unprotected telomeres and telomeric genetic diseases. These microproteins are also believed to vary in size and may be incorporated into extracellular vesicles as cargo to transmit signals to nearby cells.
Further analysis also revealed that VR is found in higher levels in some human cancer cells and in the cells of people with diseases related to defective telomeres, such as inflammatory bowel disease. Therefore, one potential application of this research is a simple blood test to determine the levels of these proteins, which could inform individuals of their biological age and provide early warnings for conditions such as cancer or inflammation.
Implications of the study
More research is needed to fully understand the role of these proteins in the cell cycle and their potential as biomarkers for disease. In addition, developing a blood test for these proteins may pose challenges, such as the need for further validation studies and potential issues with sensitivity and specificity. Despite these limitations, the findings are significant because they challenge what we previously knew about telomeres. This study is the first to show that telomeres are more complex than previously thought, having the ability to produce proteins. This discovery could have important implications for understanding aging and disease.