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Telomere length homeostasis requires that telomerase levels are limiting
Author(s) -
Cristofari Gaël,
Lingner Joachim
Publication year - 2006
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600952
Subject(s) - telomere , telomerase , biology , telomerase reverse transcriptase , telomere binding protein , reverse transcriptase , telomerase rna component , microbiology and biotechnology , germline , population , rna , dna , transcription factor , genetics , dna binding protein , gene , demography , sociology
Stabilization of telomere length in germline and highly proliferative human cells is required for long‐term survival and for the immortal phenotype of cancer‐derived cells. This is achieved through expression of telomerase reverse transcriptase (TERT), which synthesizes telomeric repeats through reverse transcription of its tightly associated RNA template (TR). The telomeric repeat binding factor TRF1 inhibits telomerase at telomeres in cis in a length‐dependent manner to achieve telomere length homeostasis. Here we manipulate telomerase activity over a wide range in cancer and primary cells. Concomitant overexpression of TERT and TR was necessary and sufficient to substantially increase telomerase activity. Upon overexpression, more telomerase associated with telomeres and telomeres elongated at a constant rate (up to 0.8 kb/population doubling (PD)) in a length‐independent manner. Thus, in less than 50 PDs, the length of telomeres increased 3–8‐fold beyond physiological size, while telomere‐bound TRF1 and TRF2 increased proportionally to telomere length. Thus, long telomeres do not permanently adopt a structural state that is non‐extendible. A low cellular concentration of telomerase is critical to achieve preferential elongation of short telomeres and telomere length homeostasis.