Genes are fundamental units of heredity, carrying instructions that determine an organism’s traits and bodily functions. A gene mutation represents a change in the DNA sequence of a gene, which can involve the addition, removal, or substitution of DNA building blocks. These alterations can disrupt the gene’s instructions, potentially leading to changes in cell function or contributing to various health conditions. Understanding gene mutations offers insights into disease origins and guides new treatment development.
Understanding the TERT Gene
The TERT gene, or telomerase reverse transcriptase, provides instructions for making a protein that is a core component of the telomerase enzyme. Telomerase helps maintain telomeres, which are repetitive DNA sequences at the ends of chromosomes. These telomeres act like protective caps, shielding genetic information from damage during cell division.
Each time a cell divides, telomeres naturally shorten. The telomerase enzyme, produced with the help of the TERT gene, counteracts this by adding new telomere repeats. This activity is important in frequently dividing cells, such as stem cells and certain immune cells, allowing them to maintain their length and continue dividing.
How TERT Mutations Occur
TERT mutations can arise through different mechanisms: inherited from parents or acquired during an individual’s lifetime. Inherited mutations, also known as germline mutations, are present in nearly every cell from birth and can be passed down. These occur when a parent carries the mutation in their egg or sperm cells.
Acquired mutations, or somatic mutations, develop in body cells after conception and are not passed on to offspring. These changes can result from errors during DNA replication or exposure to environmental factors like ultraviolet radiation or certain chemicals. For example, TERT promoter mutations are commonly observed in cancers linked to environmental exposures, such as skin and bladder cancers.
Cellular Consequences of TERT Mutations
When the TERT gene is mutated, it can lead to two main cellular consequences: either an increase or a decrease in telomerase activity. Mutations in the TERT promoter region are the most common non-coding mutations in human cancers, often leading to increased TERT transcription and telomerase activity. This overactivity allows cells to maintain telomere length, bypassing natural limits on cell division and contributing to uncontrolled cell growth, a hallmark of cancer.
Conversely, other TERT mutations can result in telomerase deficiency, causing telomeres to shorten prematurely. When telomeres become too short, cells may stop dividing (senescence) or undergo programmed cell death. This premature shortening and cellular dysfunction can impair tissue renewal, leading to aging-related problems and various diseases.
TERT Mutations and Human Health
TERT mutations have diverse impacts on human health, depending on whether they lead to increased or decreased telomerase activity. Elevated telomerase activity, often driven by TERT promoter mutations, is a common feature in many cancers, including melanoma, liver cancer, and thyroid carcinoma. These mutations allow cancer cells to continuously proliferate and grow by preventing telomere shortening. For instance, TERT promoter mutations are associated with more aggressive forms of papillary thyroid carcinoma, especially when co-occurring with other genetic changes like BRAF mutations.
Conversely, mutations in TERT that lead to reduced telomerase activity are linked to telomere biology disorders (TBDs), or telomeropathies. These disorders are characterized by abnormally short telomeres and can manifest as a wide spectrum of symptoms. Examples include dyskeratosis congenita (DC), a multisystem disorder, idiopathic pulmonary fibrosis (a severe lung disease), and aplastic anemia (a condition where the bone marrow produces too few blood cells). These conditions often arise from impaired tissue renewal due to the inability of stem cells to maintain telomere length.
Current Research and Therapeutic Insights
Understanding TERT mutations influences current research and the development of potential therapies. Researchers are exploring diagnostic tools that detect TERT mutations, which could help identify cancers or telomere biology disorders earlier. For cancers with increased telomerase activity, strategies involve developing targeted therapies that inhibit the telomerase enzyme.
These approaches include small molecules designed to bind to TERT and block its catalytic function, or immunotherapies that stimulate the immune system to target telomerase-expressing cancer cells. For telomere biology disorders, research focuses on strategies to activate telomerase. This includes restoring youthful levels of TERT to mitigate aging signs and treat age-related conditions by reducing cellular senescence, inflammation, and improving tissue function.