The Telomerase Reverse Transcriptase ($TERT$) gene contains the instructions for making a protein that is the core catalytic component of the telomerase enzyme. This enzyme is responsible for maintaining telomeres, which are repetitive DNA sequences forming protective caps at the ends of chromosomes. In most adult human cells, the $TERT$ gene is largely inactive, causing telomeres to shorten gradually as a person ages. Mutations that either increase or decrease the normal function of this gene can have profound consequences, leading to either uncontrolled cell growth or premature tissue failure.
The Role of TERT and Telomerase
Chromosomes in human cells are capped by structures called telomeres, which consist of thousands of repeats of a six-nucleotide sequence (TTAGGG) that shield genetic information from damage. These caps are often compared to the plastic tips on shoelaces because they prevent the chromosome ends from fraying or being recognized by the cell as broken DNA. During normal cell division and DNA replication, the cell’s machinery is unable to copy the very end of the linear chromosome, a phenomenon known as the end-replication problem. This results in telomeres becoming progressively shorter with each division.
If telomeres shorten to a critically small length, the cell enters a state of permanent growth arrest called senescence, or it undergoes programmed cell death. Telomerase is the specialized ribonucleoprotein enzyme complex that counteracts this shortening by adding new repeats to the telomere ends. The enzyme consists of two main components: the $TERT$ protein, which is the reverse transcriptase catalytic subunit, and a non-coding RNA molecule ($TERC$) that serves as the template for the new DNA sequence. The level of $TERT$ protein generally acts as the rate-limiting step for overall telomerase activity in the cell.
How TERT Mutations Disrupt Cell Function
Mutations in the $TERT$ gene disrupt telomere length maintenance, resulting in two outcomes: too much or too little activity. Gain-of-function mutations typically lead to the overexpression or hyperactivation of telomerase, causing telomeres to lengthen beyond their normal range. This gain of function grants the cell an extended or infinite capacity for replication, effectively bypassing the normal limits on cell division. Such mutations often involve changes in the regulatory regions of the $TERT$ gene, rather than the protein-coding sequence itself.
Conversely, loss-of-function mutations result in reduced or non-functional telomerase, which leads to accelerated telomere shortening. These mutations often occur within the protein-coding region, impairing the catalytic ability of the $TERT$ enzyme to add new repeats. Critically short telomeres trigger accelerated cellular aging, leading to early senescence or death, especially in highly proliferative tissues.
TERT Mutations and Cancer Development
The most common way $TERT$ is implicated in cancer is through somatic, gain-of-function mutations that are acquired during a person’s lifetime and are not inherited. These mutations are highly recurrent and typically occur in the non-coding promoter region of the $TERT$ gene. Specifically, two main hotspot positions, C228T and C250T, are affected.
The change from a cytosine (C) to a thymine (T) at these locations creates a novel binding site for E-twenty-six ($ETS$) transcription factors. The recruitment of $ETS$ factors dramatically increases the rate at which the $TERT$ gene is transcribed, leading to a massive overexpression of the telomerase enzyme. This overabundance of active telomerase maintains telomere length, conferring cellular immortality—a defining characteristic of malignant transformation. $TERT$ promoter mutations are among the most frequent alterations in human cancers, found in up to 83% of glioblastomas, 71% of melanomas, 66% of bladder cancers, and 47% of hepatocellular carcinomas. The presence of these mutations is often associated with a more aggressive disease and a poorer prognosis across various tumor types.
TERT Mutations in Inherited Telomere Disorders
In contrast to cancer, inherited disorders linked to $TERT$ are caused by germline, loss-of-function mutations present in every cell from birth, resulting in reduced or eliminated telomerase activity. The consequence is critically short telomeres across all tissues, which particularly affects organs with high cellular turnover, where constant cell division is required for regeneration.
One of the most recognized conditions caused by these defects is Dyskeratosis Congenita ($DC$), a multi-system disorder characterized by abnormal skin pigmentation, nail dystrophy, and a high risk of bone marrow failure. Mutations in $TERT$ are also a known cause of severe Aplastic Anemia, where the body fails to produce enough new blood cells, and Idiopathic Pulmonary Fibrosis, a progressive scarring of the lungs. The severity of these telomere biology disorders can increase in successive generations, a phenomenon called genetic anticipation, because each generation inherits an already shortened telomere length on top of the genetic defect.