Telomerase

Telomerase is a large ribonucleoprotein complex composed of a catalytic protein subunit (telomerase reverse transcriptase, TERT) and an RNA component (telomerase RNA component, TERC) that contains the template for synthesizing telomeric repeats. The enzyme uses its RNA template to add short, G-rich sequences—such as TTAGGG in humans—to the 3' end of chromosomes, thereby extending the telomere. This process is highly processive, meaning the enzyme can add multiple repeats in a single binding event, and it is regulated by accessory proteins such as dyskerin and TCAB1 that stabilize the complex and facilitate its localization to Cajal bodies. The reverse transcriptase activity is distinct from that of retroviral reverse transcriptases in that it uses an intrinsic RNA template rather than an external one.

Telomerase is active in germ cells, stem cells, and most cancer cells, but is repressed in most somatic tissues, leading to progressive telomere shortening with each cell division. This shortening acts as a mitotic clock that triggers replicative senescence or apoptosis when telomeres become critically short, a key mechanism in cellular aging. Telomerase activity is tightly regulated at multiple levels, including transcriptional control of TERT, alternative splicing, and post-translational modifications. In addition to its canonical role in telomere maintenance, telomerase has non-canonical functions, such as enhancing cell proliferation and protecting mitochondria from oxidative stress, which are independent of its enzymatic activity.

Because telomerase is reactivated in approximately 85–90% of human cancers, it is an attractive target for cancer therapy. Inhibitors such as imetelstat, a lipid-conjugated oligonucleotide that binds to the RNA template, have been tested in clinical trials for myelofibrosis and other malignancies. Conversely, telomerase activation has been proposed as a strategy to treat age-related diseases and degenerative disorders, with small-molecule activators like TA-65 showing promise in preclinical models. Mutations in telomerase components cause telomere biology disorders, including dyskeratosis congenita, idiopathic pulmonary fibrosis, and aplastic anemia, which are characterized by premature telomere shortening and stem cell failure.

Telomerase was first discovered in Tetrahymena, a single-celled organism that maintains its telomeres through a unique process of chromosome fragmentation and de novo telomere addition. Unlike most eukaryotes, some insects, such as silkworms, use transposable elements instead of telomerase to maintain chromosome ends. Telomerase is also present in plants, where it plays a role in meristem development, and in some archaea, which possess a simplified version of the enzyme. A notable edge case is the naked mole-rat, which expresses telomerase in its somatic cells and exhibits exceptional longevity, yet does not develop cancer—a phenomenon that challenges the simple view of telomerase as a cancer promoter. Additionally, telomerase activity has been detected in human embryos only at the blastocyst stage, and its regulation during development remains an active area of research.

Telomere

A repetitive DNA sequence at chromosome ends that protects them from degradation and fusion.

TERT

Telomerase reverse transcriptase, the catalytic protein subunit of telomerase.

TERC

Telomerase RNA component, which contains the template for telomere synthesis.

Replicative senescence

The irreversible arrest of cell division triggered by critically short telomeres.