BACKGROUND: Eukaryotic chromosomes end with telomeres, which in most organisms are composed of tandem DNA repeats associated with telomeric proteins. These DNA repeats are synthesized by the enzyme telomerase, whose activity in most human tissues is tightly regulated, leading to gradual telomere shortening with cell divisions. Shortening beyond a critical length causes telomere uncapping, manifested by the activation of a DNA damage response (DDR) and consequently cell cycle arrest. Thus, telomere length limits the number of cell divisions and provides a tumor-suppressing mechanism. However, not only telomere shortening, but also damaged telomere structure, can cause telomere uncapping. Dyskeratosis Congenita (DC) and its severe form Hoyeraal-Hreidarsson Syndrome (HHS) are genetic disorders mainly characterized by telomerase deficiency, accelerated telomere shortening, impaired cell proliferation, bone marrow failure, and immunodeficiency. METHODOLOGY/PRINCIPAL FINDINGS: We studied the telomere phenotypes in a family affected with HHS, in which the genes implicated in other cases of DC and HHS have been excluded, and telomerase expression and activity appears to be normal. Telomeres in blood leukocytes derived from the patients were severely short, but in primary fibroblasts they were normal in length. Nevertheless, a significant fraction of telomeres in these fibroblasts activated DDR, an indication of their uncapped state. In addition, the telomeric 3' overhangs are diminished in blood cells and fibroblasts derived from the patients, consistent with a defect in telomere structure common to both cell types. CONCLUSIONS/SIGNIFICANCE: Altogether, these results suggest that the primary defect in these patients lies in the telomere structure, rather than length. We postulate that this defect hinders the access of telomerase to telomeres, thus causing accelerated telomere shortening in blood cells that rely on telomerase to replenish their telomeres. In addition, it activates the DDR and impairs cell proliferation, even in cells with normal telomere length such as fibroblasts. This work demonstrates a telomere length-independent pathway that contributes to a telomere dysfunction disease.
BACKGROUND: Eukaryotic chromosomes end with telomeres, which in most organisms are composed of tandem DNA repeats associated with telomeric proteins. These DNA repeats are synthesized by the enzyme telomerase, whose activity in most human tissues is tightly regulated, leading to gradual telomere shortening with cell divisions. Shortening beyond a critical length causes telomere uncapping, manifested by the activation of a DNA damage response (DDR) and consequently cell cycle arrest. Thus, telomere length limits the number of cell divisions and provides a tumor-suppressing mechanism. However, not only telomere shortening, but also damaged telomere structure, can cause telomere uncapping. Dyskeratosis Congenita (DC) and its severe form Hoyeraal-Hreidarsson Syndrome (HHS) are genetic disorders mainly characterized by telomerase deficiency, accelerated telomere shortening, impaired cell proliferation, bone marrow failure, and immunodeficiency. METHODOLOGY/PRINCIPAL FINDINGS: We studied the telomere phenotypes in a family affected with HHS, in which the genes implicated in other cases of DC and HHS have been excluded, and telomerase expression and activity appears to be normal. Telomeres in blood leukocytes derived from the patients were severely short, but in primary fibroblasts they were normal in length. Nevertheless, a significant fraction of telomeres in these fibroblasts activated DDR, an indication of their uncapped state. In addition, the telomeric 3' overhangs are diminished in blood cells and fibroblasts derived from the patients, consistent with a defect in telomere structure common to both cell types. CONCLUSIONS/SIGNIFICANCE: Altogether, these results suggest that the primary defect in these patients lies in the telomere structure, rather than length. We postulate that this defect hinders the access of telomerase to telomeres, thus causing accelerated telomere shortening in blood cells that rely on telomerase to replenish their telomeres. In addition, it activates the DDR and impairs cell proliferation, even in cells with normal telomere length such as fibroblasts. This work demonstrates a telomere length-independent pathway that contributes to a telomere dysfunction disease.
Authors: Sheila A Stewart; Ittai Ben-Porath; Vincent J Carey; Benjamin F O'Connor; William C Hahn; Robert A Weinberg Journal: Nat Genet Date: 2003-03-24 Impact factor: 38.330
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Authors: Jan Karlseder; Kristina Hoke; Olga K Mirzoeva; Christopher Bakkenist; Michael B Kastan; John H J Petrini; Titia de Lange Journal: PLoS Biol Date: 2004-08-17 Impact factor: 8.029
Authors: Zhong Deng; Galina Glousker; Aliah Molczan; Alan J Fox; Noa Lamm; Jayaraju Dheekollu; Orr-El Weizman; Michael Schertzer; Zhuo Wang; Olga Vladimirova; Jonathan Schug; Memet Aker; Arturo Londoño-Vallejo; Klaus H Kaestner; Paul M Lieberman; Yehuda Tzfati Journal: Proc Natl Acad Sci U S A Date: 2013-08-19 Impact factor: 11.205
Authors: Judith C W Marsh; Fernanda Gutierrez-Rodrigues; James Cooper; Jie Jiang; Shreyans Gandhi; Sachiko Kajigaya; Xingmin Feng; Maria Del Pilar F Ibanez; Flávia S Donaires; João P Lopes da Silva; Zejuan Li; Soma Das; Maria Ibanez; Alexander E Smith; Nicholas Lea; Steven Best; Robin Ireland; Austin G Kulasekararaj; Donal P McLornan; Anthony Pagliuca; Isabelle Callebaut; Neal S Young; Rodrigo T Calado; Danielle M Townsley; Ghulam J Mufti Journal: Blood Adv Date: 2018-01-04