Telomere attrition and dysfunction: a potential trigger of the progeroid phenotype in nijmegen breakage syndrome

• Published in: Aging (Albany, NY.) Vol. 12; no. 12; pp. 12342 - 12375
• Main Authors: Habib, Raneem, Kim, Ryong, Neitzel, Heidemarie, Demuth, Ilja, Chrzanowska, Krystyna, Seemanova, Eva, Faber, Renaldo, Digweed, Martin, Voss, Reinhard, Jäger, Kathrin, Sperling, Karl, Walter, Michael
• Format: Journal Article
• Language: English
• Published: United States Impact Journals 20.06.2020
• Subjects: Adolescent; Animals; Cell Cycle Proteins - genetics; Cell Line, Tumor; Child; Child, Preschool; Disease Models, Animal; Female; Heterozygote; Homozygote; Humans; Infant; Karyotyping; Male; Mice; Mice, Transgenic; Nijmegen Breakage Syndrome - complications; Nijmegen Breakage Syndrome - genetics; Nijmegen Breakage Syndrome - pathology; Nuclear Proteins - genetics; Progeria - genetics; Progeria - pathology; Research Paper; Telomerase - metabolism; Telomere - pathology; Telomere Homeostasis - genetics; Young Adult; telomere-position effect over long distances; nibrin; alternative lengthening of telomeres; DNA repair; nijmegen breakage syndrome
• ISSN: 1945-4589; 1945-4589
• DOI: 10.18632/aging.103453

Nibrin, as part of the NBN/MRE11/RAD50 complex, is mutated in Nijmegen breakage syndrome (NBS), which leads to impaired DNA damage response and lymphoid malignancy. Telomere length (TL) was markedly reduced in homozygous patients (and comparably so in all chromosomes) by ~40% (qPCR) and was slightly reduced in NBS heterozygotes older than 30 years (~25% in qPCR), in accordance with the respective cancer rates. Humanized cancer-free NBS mice had normal TL. Telomere elongation was inducible by telomerase and/or alternative telomere lengthening but was associated with abnormal expression of telomeric genes involved in aging and/or cell growth. Lymphoblastoid cells from NBS patients with long survival times (>12 years) displayed the shortest telomeres and low caspase 7 activity. NBS is a secondary telomeropathy. The two-edged sword of telomere attrition enhances the cancer-prone situation in NBS but can also lead to a relatively stable cellular phenotype in tumor survivors. Results suggest a modular model for progeroid syndromes with abnormal expression of telomeric genes as a molecular basis. We studied TL and function in 38 homozygous individuals, 27 heterozygotes, one homozygous fetus, six NBS lymphoblastoid cell lines, and humanized NBS mice, all with the same founder mutation: c.657_661del5.