How chromosome ends avoid shortening each time they are copied was a long-standing puzzle called the “end-replication problem.” Using the ciliate Tetrahymena and yeast, the laureates showed that the ends contain short repeated DNA called telomeres and that telomerase adds new repeats, solving the problem. Telomerase is a ribonucleoprotein enzyme that uses an internal RNA as a template to extend DNA. This mechanism is conserved from single-celled organisms to humans; when telomeres become too short, cells enter replicative senescence. Because telomere maintenance permits cancer cells to divide indefinitely and helps stem cells renew, the discovery opened paths to medical and pharmaceutical research.

Telomeres consist of tandem 5′-TTAGGG-3′ repeats that extend several kilobases at the termini of eukaryotic chromosomes. During replication, removal of the RNA primer on the lagging strand leaves a gap, theoretically shortening telomeres by 50–200 bp each cell cycle. The telomerase holoenzyme, composed of telomerase reverse transcriptase (TERT) and an RNA component (TERC), solves this by copying a CAAUCCCAA… motif within TERC to add G-rich repeats to the 3′ overhang. After extension, DNA polymerase α/primase fills the complementary strand, and the Shelterin complex (TRF1/2, POT1, etc.) folds the end into a T-loop, hiding it from nucleases and DNA-damage sensors. Telomere shortening triggers replicative senescence and genome instability, providing tumor-suppressive pressure, whereas telomerase reactivation occurs in >90 % of cancers and represents a therapeutic target. Telomere length also serves as a biomarker for stem-cell capacity, tissue regeneration, and age-related diseases.

The work was groundbreaking in demonstrating the evolutionary conservation of telomere repeats and in identifying telomerase as a novel RNP. Tetrahymena telomerase, first characterized by Greider & Blackburn, consists of catalytic TERT, TER RNA, Sm proteins, p65, and other cofactors; BRET and single-molecule studies support a repeat-addition processivity model in which the enzyme adds six nucleotides and then translocates. Template boundary elements and stem-loop IV/V in TER RNA are essential for repeat-number fidelity, while yeast Est1/3 and human TCAB1 coordinate in-vivo recruitment. Within Shelterin, TIN2/TPP1 modulate telomerase access and POT1’s OB-fold acts as a TelSSB that specifically coats the G-overhang. Emerging data reveal non-canonical roles of TERT, including Wnt/β-catenin transcriptional activation, mitochondrial localization, and formation of an RNA-dependent RNA polymerase with RMRP, indicating that telomere biology intersects with epigenetics, metabolism, and developmental programs.