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

Background: 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. Results: 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. Conclusions: 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. Methods: 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 NBN mutation: c.657_661del5.

• Publication year

  2020

• Venue

  Aging

• Publication date

  2020-06-20

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.18632/aging.103453PMID 32564008PMCID 7343506
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2019cited by this paper
• Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson–Gilford Progeria Syndrome

  2019cited by this paper
• Mechanisms and functions of cellular senescence.

  2018influential reference
• Activation of JNK signaling in osteoblasts is inversely correlated with collagen synthesis in age-related osteoporosis.

  2018cited by this paper
• Role of the Mre11 Complex in Preserving Genome Integrity

  2018cited by this paper
• Evidence for a pre-malignant cell line in a skin biopsy from a patient with Nijmegen breakage syndrome

  2018cited by this paper
• SCAMP4 enhances the senescent cell secretome

  2018influential reference
• Telomere-associated aging disorders.

  2017cited by this paper
• Correlation of Leukocyte Telomere Length Measurement Methods in Patients with Dyskeratosis Congenita and in Their Unaffected Relatives

  2017cited by this paper
• PIM1 induces cellular senescence through phosphorylation of UHRF1 at Ser311

  2017influential reference
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  2017cited by this paper
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  2017cited by this paper
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  2017influential reference
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• Effects of age-related loss of P/Q-type calcium channels in a mice model of peripheral nerve injury.

  2015cited by this paper
• Telomere position effect: regulation of gene expression with progressive telomere shortening over long distances

  2014influential reference
• Telomeropathies: An emerging spectrum disorder

  2014cited by this paper
• Olfactomedin proteins: central players in development and disease

  2014cited by this paper
• Radiation-induced telomere length variations in normal and in Nijmegen Breakage Syndrome cells

  2014cited by this paper
• Cell biology of disease Telomeropathies : An emerging spectrum disorder

  2014cited by this paper
• Alternative lengthening of telomeres: recurrent cytogenetic aberrations and chromosome stability under extreme telomere dysfunction.

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• Notch3 functions as a tumor suppressor by controlling cellular senescence.

  2013cited by this paper
• Skp2 E3 ligase integrates ATM activation and homologous recombination repair by ubiquitinating NBS1.

  2012influential reference
• Nijmegen breakage syndrome (NBS)

  2012cited by this paper
• DNA Damage in Nijmegen Breakage Syndrome Cells Leads to PARP Hyperactivation and Increased Oxidative Stress

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• Analysis of telomere length in patients with chromosomal instability syndromes, particularly Nijmegen Breakage Syndrome (NBS) and its mouse model by complementary technologies

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• Alternative lengthening of telomeres: models, mechanisms and implications

  2010influential reference
• Assoziationsstudie zur klinischen Variabilität bei Patienten mit dem Nijmegen Breakage Syndrom

  2010cited by this paper
• The Mre11 Complex and the Response to Dysfunctional Telomeres

  2009cited by this paper
• A Systematic Proteomic Study of Irradiated DNA Repair Deficient Nbn-Mice

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• Cell Cycle-Dependent Role of MRN at Dysfunctional Telomeres: ATM Signaling-Dependent Induction of Nonhomologous End Joining (NHEJ) in G1 and Resection-Mediated Inhibition of NHEJ in G2

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• DNA‐Repair Deficiency and Cancer: Lessons from Lymphoma

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• Cardiac structure and function during ageing in energetically compromised Guanidinoacetate N-methyltransferase (GAMT)-knockout mice – a one year longitudinal MRI study

  2008influential reference
• Cardiac-restricted overexpression of extracellular matrix metalloproteinase inducer causes myocardial remodeling and dysfunction in aging mice.

  2008cited by this paper
• Short telomeres in aggressive non-Hodgkin's lymphoma as a risk factor in lymphomagenesis.

  2007cited by this paper
• Xrcc3 and Nbs1 are required for the production of extrachromosomal telomeric circles in human alternative lengthening of telomere cells.

  2007cited by this paper
• The clinical manifestation of a defective response to DNA double-strand breaks as exemplified by Nijmegen breakage syndrome

  2007cited by this paper
• Cancer risk of heterozygotes with the NBN founder mutation.

  2007cited by this paper
• Ataxia telangiectasia mutated (Atm) is not required for telomerase-mediated elongation of short telomeres

  2006cited by this paper
• Genetic modulation of senescent phenotypes in Homo sapiens.

  2005cited by this paper
• Functional human telomeres are recognized as DNA damage in G2 of the cell cycle.

  2005cited by this paper
• Role of Nbs1 in the activation of the Atm kinase revealed in humanized mouse models

  2005influential reference
• Shared phenotypes among segmental progeroid syndromes suggest underlying pathways of aging.

  2005cited by this paper
• Nijmegen breakage syndrome: clinical manifestation of defective response to DNA double-strand breaks.

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• Assembly of functional ALT-associated promyelocytic leukemia bodies requires Nijmegen Breakage Syndrome 1.

  2003cited by this paper
• Role of telomeres and telomerase in the pathogenesis of human cancer.

  2003cited by this paper
• Telomere maintenance and cell cycle regulation in spontaneously immortalized T-cell lines from Nijmegen breakage syndrome patients.

  2003cited by this paper
• DNA damage foci at dysfunctional telomeres.

  2003cited by this paper
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  2003influential reference
• Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products

  2000cited by this paper
• Preferential accumulation of single-stranded regions in telomeres of human fibroblasts.

  1998cited by this paper
• Expression of TERT in early premalignant lesions and a subset of cells in normal tissues

  1998cited by this paper
• Synchrony in telomere length of the human fetus

  1998cited by this paper
• Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome.

  1998cited by this paper
• Telomere shortening and tumor formation by mouse cells lacking telomerase RNA.

  1997cited by this paper
• The gene for the ataxia-telangiectasia variant, Nijmegen breakage syndrome, maps to a 1-cM interval on chromosome 8q21.

  1997cited by this paper
• Heterogeneity in telomere length of human chromosomes.

  1996cited by this paper
• Developmental and tissue-specific regulation of mouse telomerase and telomere length.

  1995cited by this paper
• A routine method for the establishment of permanent growing lymphoblastoid cell lines

  1986cited by this paper
• A NEW CHROMOSOMAL INSTABILITY DISORDER: THE NIJMEGEN BREAKAGE SYNDROME

  1981cited by this paper
• Genetic syndromes in man with potential relevance to the pathobiology of aging.

  1978cited by this paper

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