title: Diminished telomeric 3' overhangs are associated with telomere dysfunction in Hoyeraal-Hreidarsson syndrome.
abstract: 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.
  
  
  RESULTS
  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
  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.affiliation: Department of Genetics, The Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, Jerusalem, Israel.
authors.forename: Noa
authors.initials: N
authors.lastname: Lamm
authors.forename: Elly
authors.initials: E
authors.lastname: Ordan
authors.forename: Rotem
authors.initials: R
authors.lastname: Shponkin
authors.forename: Carmelit
authors.initials: C
authors.lastname: Richler
authors.forename: Memet
authors.initials: M
authors.lastname: Aker
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Tzfati
mesh_terms: D000328:Adult; D001773:Blood Cells / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D019871:Dyskeratosis Congenita / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D004789:Enzyme Activation; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D012313:RNA / Q000378:metabolism; D035781:Siblings; D012867:Skin / Q000201:enzymology / Q000473:pathology; D013577:Syndrome; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000378:metabolism*
chemical_list: C422952:telomerase RNA; D012313:RNA; C509186:TERT protein, human; D019098:Telomerase