[HTML][HTML] Telomere dynamics in dyskeratosis congenita: the long and the short of iPS

S Agarwal, GQ Daley - Cell research, 2011 - nature.com
S Agarwal, GQ Daley
Cell research, 2011nature.com
Seminal experiments by Hayflick in the 1960s demonstrated that normal human diploid cells
have a finite replicative life span in culture [1]. The Hayflick “limit” is explained at least in part
by the decay in telomeres, repeat sequences that cap the ends of chromosomes [2].
Telomeric repeats are only incompletely extended by DNA polymerase and thus erode with
each cell division. When telomeres become critically short, cells stop dividing and senesce.
The telomere length in somatic cells is an “endowment” inherited from the stem cells from …
Seminal experiments by Hayflick in the 1960s demonstrated that normal human diploid cells have a finite replicative life span in culture [1]. The Hayflick “limit” is explained at least in part by the decay in telomeres, repeat sequences that cap the ends of chromosomes [2]. Telomeric repeats are only incompletely extended by DNA polymerase and thus erode with each cell division. When telomeres become critically short, cells stop dividing and senesce. The telomere length in somatic cells is an “endowment” inherited from the stem cells from which they derive. Stem cells contain telomerase, a multisubunit ribonucleoprotein polymerase that adds repeats to telomere ends and thereby counteracts telomere attrition and replicative senescence, allowing stem cells to self-renew and maintain adult tissues throughout life. Unlike most telomerase components, the telomerase reverse transcriptase (TERT) is absent in somatic cells, and therefore the gatekeeper of telomerase function. TERT is expressed in highly self-renewing or immortalized cells such as embryonic cells, germ cells, cancer cells, and some adult stem cells, and forced expression of TERT in somatic cells overcomes replicative senescence and contributes to malignant transformation. Reprogramming of somatic cells to an embryonic state by nuclear transfer or factor-mediated direct reprogramming activates TERT, and is associated with the acquisition of self-renewal capacity [3, 4]. Dramatic support for the theory that aging of cells and tissues and perhaps even the whole organism depends on telomere length comes from study of the human premature aging syndrome dyskeratosis congenita (DC). The skin and mucosal lesions for which DC is named are the outward manifestations of a systemic degenerative disorder characterized by a propensity for bone marrow failure, pulmonary fibrosis, hematologic and epithelial malignancy, and other pleiotropic defects. In the past 12 years, elegant studies have revealed mutations in seven genes as a cause of DC, all of which encode telomerase
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