TERT (telomerase reverse transcriptase; HGNC:11730, NCBI Gene ID 7015) is a human locus mapped to chromosome band 5p15.33 that encodes telomerase ribonucleoprotein catalytic reverse transcriptase subunit hTERT (1,132 aa; 127 kDa; EC 2.7.7.49). TERT acts in RNA-templated (TERC) de novo addition of 5-prime-TTAGGG-3-prime telomeric hexamer repeats to chromosome 3-prime ends, together with TERC (Telomerase RNA Component Template Gene), TP53 (Activated by Critically Short Uncapped Telomeres), and CDKN1A (p21 Replicative Senescence Effector Gene). Encodes the rate-limiting catalytic reverse transcriptase subunit of telomerase, counteracting telomere attrition in stem cells and reactivated in ~85–90% of cancers.
Genomic Organization & Cytogenetic Locus: 16-exon gene located near the distal tip of chromosome 5p15.33 (1.2 Mb from the telomere), featuring a GC-rich TATA-less promoter normally silenced upon somatic differentiation and encoding four conserved structural domains: the Telomerase Essential N-terminal (TEN) domain, the Telomerase RNA-Binding Domain (TRBD), the central Reverse Transcriptase (RT) palm/fingers catalytic domain (harboring the Asp712-Asp868-Asp869 triad), and the C-terminal thumb extension.
Cellular & Tissue Expression Profile: Expressed in human totipotent zygotes, embryonic stem cells, germline spermatogonia, adult hematopoietic stem cells, activated T and B lymphocytes, and intestinal crypt base stem cells, but transcriptionally silenced in most adult post-mitotic and somatic fibroblasts—establishing the Hayflick replicative senescence limit.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Assembles in Cajal bodies with the non-coding Telomerase RNA Component (TERC, which provides the 11-nucleotide 5-prime-CUAACCCUAAC-3-prime template) and dyskerin (DKC1) to form the active telomerase holoenzyme; recruited to chromosome ends during S phase by the shelterin protein TPP1 (ACD), TERT reverse-transcribes iterative 5-prime-TTAGGG-3-prime hexamers onto the 3-prime single-stranded G-overhang to compensate for the end-replication problem and prevent ATM/ATR-p53-p21 replicative senescence.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Telomerase, the enzyme TERT catalyzes, was identified by Carol Greider and Elizabeth Blackburn, who shared the 2009 Nobel Prize in Physiology or Medicine with Jack Szostak for discovering how telomeres and telomerase protect chromosomes; heterozygous germline loss-of-function mutations cause autosomal dominant short-telomere syndromes including Dyskeratosis Congenita, familial idiopathic pulmonary fibrosis (where TERT is the single most common monogenic cause), and aplastic anemia; conversely, somatic point mutations in the TERT core promoter (-124C>T / C228T and -146C>T / C250T) create de novo ETS/GABPA transcription factor binding sites and are the most common non-coding driver mutations in human melanoma, glioblastoma, urothelial bladder cancer, and hepatocellular carcinoma.
Therapeutic & Clinical Pharmacology: Targeted in oncology by the FDA-approved lipid-conjugated oligonucleotide telomerase inhibitor imetelstat (Rytelo, approved in 2024 for myelodysplastic syndromes), while transient non-integrating TERT mRNA delivery or AAV9-TERT gene therapy is investigated in short-telomere pulmonary fibrosis and progeroid syndromes.