diminished telomeric 3′ overhangs are associated with telomere dysfunction in hoyeraal-hreidarsson syndrome悬臂下降3u2032端粒与端粒功能障碍hoyeraal-hreidarsson综合症.pdfVIP

Diminished Telomeric 39 Overhangs Are Associated with Telomere Dysfunction in Hoyeraal-Hreidarsson Syndrome 1 1,3 1 1 2 1 Noa Lamm , Elly Ordan , Rotem Shponkin , Carmelit Richler , Memet Aker , Yehuda Tzfati * 1 Department of Genetics, The Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, Jerusalem, Israel, 2 Department of Pediatric Hematology-Oncology, Hadassah University Hospital, Ein Kerem, Jerusalem, Israel, 3 Department of Biochemistry, The Hebrew University-Hadassah Medical School, Ein Kerem, Jerusalem, Israel 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. 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