Telomerase (TERT)
Telomerase is the ribonucleoprotein enzyme that extends telomeres: it uses its own RNA template to add repetitive DNA to chromosome ends, reversing the shortening that ordinary replication imposes.
Function
Linear chromosomes shorten at each S phase because DNA polymerase cannot fully replicate a strand’s 3′ end — the “end replication problem”. Telomerase, whose catalytic subunit is TERT and whose RNA component (TERC) supplies the template, is a reverse transcriptase that binds the telomere’s 3′ overhang and extends it with TTAGGG repeats. Germ cells, stem cells, and activated lymphocytes express telomerase; most somatic cells repress it after development and pay for each division with telomere length. When telomeres become critically short, the cell activates p53-dependent senescence — the Hayflick limit — or, if checkpoints fail, undergoes telomere crisis with chromosome fusions and catastrophic genome rearrangement.
In cancer
About ninety percent of human tumors maintain telomeres, and the mechanism is usually TERT promoter mutation — two recurrent mutations that create ETS transcription-factor binding sites and reactivate TERT expression, among the most common promoter mutations in cancer. The alternative (ALT) route uses recombination-based telomere extension. Telomerase is therefore near-universal in cancer and near-absent in somatic tissue, which makes it an attractive drug target; telomerase inhibitors (imetelstat) are in trials in myelofibrosis.
Notes
- Human gene symbol: TERT; UniProt O14746; 1,132 amino acids; reverse transcriptase; co-assembles with TERC RNA and accessory proteins.
- Elizabeth Blackburn, Carol Greider, and Jack Szostak received the 2009 Nobel Prize for telomerase.