{"entity":{"id":"telomere-maintenance","kind":"pathway","name":"Telomere maintenance & replicative immortality","aka":[],"tldr":"Normal cells can divide only a limited number of times because the protective caps on their chromosomes, telomeres, wear down. About 90% of cancers switch the cap-rebuilding enzyme telomerase back on, often through TERT promoter mutations, and roughly 10% use an alternative lengthening route (ALT), so they divide indefinitely; imetelstat is the first approved telomerase inhibitor.","summary":"About 90% of cancers reactivate telomerase (TERT), often via TERT promoter mutations (glioblastoma, melanoma, bladder, thyroid) or amplification; ~10% use alternative lengthening of telomeres (ALT) through homologous recombination, associated with ATRX/DAXX loss (sarcomas, pancreatic NETs, gliomas). Telomerase inhibition (imetelstat, an oligonucleotide) reached approval in lower-risk MDS (2024) and is in phase 3 in myelofibrosis; ALT cells are sensitive to ATR inhibition. TERT promoter mutation is a diagnostic and prognostic marker and a candidate for ctDNA detection in bladder cancer and glioma.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Telomerase","links":[{"label":"Shay & Wright, Telomeres and telomerase: three decades of progress (Nature Reviews Genetics 2019)","url":"https://doi.org/10.1038/s41576-019-0099-1"}],"tags":["mechanism"],"related":[],"cancers":[],"sections":[],"technologies":[],"targets":["atr"],"drugs":[],"companies":[],"institutions":["johns-hopkins","dana-farber","ucsf"],"pathways":["replication-stress","senescence"],"terms":["tert-promoter","enabling-replicative-immortality"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-shay-nat-rev-genet"],"journals":[],"dependsOn":[],"notes":["Leading programmes: Greider (Johns Hopkins, Nobel 2009); Meyerson (Dana-Farber) on TERT promoter genetics; Costello (UCSF) on TERT in glioma; Reddel (CMRI Sydney) on ALT."],"analogy":"The plastic tips on shoelaces fray a little every time you tie them; when they are gone the lace unravels and the shoe is thrown out. Cancer cells carry a machine that keeps re-tipping the laces.","nodes":[{"id":"div","label":"Each division shortens telomeres","x":15,"y":30},{"id":"crisis","label":"Senescence / crisis","x":45,"y":30},{"id":"tert","label":"TERT reactivation (promoter mutation)","x":45,"y":70},{"id":"alt","label":"ALT (ATRX/DAXX loss)","x":80,"y":70},{"id":"immortal","label":"Replicative immortality","x":80,"y":30},{"id":"atr","label":"ATR dependence (ALT)","x":92,"y":90,"targetId":"atr"}],"edges":[{"from":"div","to":"crisis","type":"activates"},{"from":"tert","to":"crisis","type":"inhibits"},{"from":"alt","to":"crisis","type":"inhibits"},{"from":"tert","to":"immortal","type":"activates"},{"from":"alt","to":"immortal","type":"activates"},{"from":"alt","to":"atr","type":"activates"}],"interventions":["Imetelstat (telomerase inhibitor) approved in MDS (2024); solid-tumour use unproven","ATR inhibitors in ALT-positive tumours","TERT promoter mutation as a urine/plasma biomarker (bladder, glioma)"]},"route":"/pathways/telomere-maintenance/","neighbours":{"target":[{"id":"atr","kind":"target","name":"ATR","route":"/targets/atr/"},{"id":"atrx","kind":"target","name":"ATRX","route":"/targets/atrx/"},{"id":"daxx","kind":"target","name":"DAXX","route":"/targets/daxx/"},{"id":"tert","kind":"target","name":"TERT","route":"/targets/tert/"}],"institution":[{"id":"dana-farber","kind":"institution","name":"Dana-Farber Brigham Cancer Center","route":"/institutions/dana-farber/"},{"id":"johns-hopkins","kind":"institution","name":"Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center","route":"/institutions/johns-hopkins/"},{"id":"ucsf","kind":"institution","name":"UCSF Helen Diller Family Comprehensive Cancer Center","route":"/institutions/ucsf/"}],"pathway":[{"id":"senescence","kind":"pathway","name":"Cellular senescence","route":"/pathways/senescence/"},{"id":"replication-stress","kind":"pathway","name":"DNA replication stress","route":"/pathways/replication-stress/"}],"term":[{"id":"enabling-replicative-immortality","kind":"term","name":"Hallmark: enabling replicative immortality","route":"/terms/enabling-replicative-immortality/"},{"id":"hallmarks-synthesis","kind":"term","name":"Hallmarks of cancer as a synthesis of the theories","route":"/terms/hallmarks-synthesis/"},{"id":"tert-promoter","kind":"term","name":"TERT promoter mutation","route":"/terms/tert-promoter/"}],"paper":[{"id":"paper-shay-nat-rev-genet","kind":"paper","name":"Telomeres and telomerase: three decades of progress","route":"/key-papers/paper-shay-nat-rev-genet/"}],"technology":[{"id":"rejuv-age-epigenetic-clocks","kind":"technology","name":"Epigenetic age after cancer treatment","route":"/technologies/rejuv-age-epigenetic-clocks/"},{"id":"rejuv-age-telomere-length","kind":"technology","name":"Telomere length after treatment","route":"/technologies/rejuv-age-telomere-length/"}]}}