Microscopy image showing fluorescent signals (bright red spots) marking telomeres in human cells (inside nucleus, blue). Image credit: Sengupta et al. (CC BY 4.0)
Human cells typically have 23 pairs of structures known as chromosomes, each containing a unique set of genes that provides the instructions needed to make proteins and other essential molecules found in the body.
At the end of each chromosome lies a region of repetitive DNA sequences, known as the telomere, which protects the chromosome strands from damage or tangling. Every time a cell divides, some of the telomere repeats are cut off, causing the telomeres to shorten. Specific enzymes known as telomerases can add these repeats back on so that the telomeres do not become too short.
As we age, telomeres naturally shorten in length, but certain lifestyle factors can accelerate this process, leading to programmed cell death and contributing to various diseases, including cancers.
In 2018, researchers showed that TRF2, a key telomere protein, helps relay information about telomere length to various regulatory genes. However, it remained unclear whether TRF2 could directly communicate this information to the telomerase itself. Sengupta et al. – including several of the researchers from the 2018 study – set out to answer this question by studying multiple human cancer cell lines with different telomere lengths.
They discovered that TRF2 acts like a messenger that interacts with the telomerase gene TERT, in a length-dependent manner. When telomeres were long, most TRF2 remained bound at the telomeres and did not interact with TERT, allowing continued telomerase activity and telomere elongation. By contrast, when telomeres were short, TRF2 was released from the telomeres and bound directly to the TERT promoter. There, together with a DNA structure called the G-quadruplex, TRF2 suppressed TERT expression and thereby limited further telomere extension. In other words, shortened telomeres repressed TERT expression, while elongated ones increased it.
In this positive feedback–like reinforcement system, telomere length is signaled by the amount of free TRF2 protein. When TERT expression is high and telomeres are long, less TRF2 is available to bind the TERT promoter, reducing repression and thereby maintaining its expression. Conversely, when TERT expression is low and telomeres are short, more TRF2 is available, reinforcing repression and sustaining the low-expression state.
Regulating telomere length is essential for healthy cell function, and its dysregulation is a hallmark of cancer. Sengupta et al. demonstrated that TRF2 plays a critical role in this process by feeding back information about telomere length directly to the TERT gene. By further dissecting this feedback system and refining experimental tools, researchers may gain new insights into telomere regulation in cancer and related diseases.
