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

Abstract

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.

A conserved long-distance telomeric silencing mechanism suppresses mTOR signaling in aging human fibroblasts

“…As a prerequisite for an overall positive net effect (tumor suppression for a sufficiently long period of time), possible negative aspects of replicative aging must be minimized. Telomere attrition is, genetic instability syndromes ( 56 ) notwithstanding, generally not life-threatening in humans and also not in mice nor in C. elegans ( 57 – 59 ).…”

“…Because of the early death of patients with HGP, it cannot entirely be ruled out that an increased risk of cancer could arise with older age in these patients. To investigate telomere clinical phenotype interrelationships more closely, cells from patients with Nijmegen breakage syndrome ( 56 ), which is characterized by chromosome instability, could be helpful. In fibroblasts from these patients, there were also indications of telomeric imbalances in TPE-OLD associated with accelerated telomere attrition ( 56 ).…”

“…To investigate telomere clinical phenotype interrelationships more closely, cells from patients with Nijmegen breakage syndrome ( 56 ), which is characterized by chromosome instability, could be helpful. In fibroblasts from these patients, there were also indications of telomeric imbalances in TPE-OLD associated with accelerated telomere attrition ( 56 ). The patients tend to have progeroid symptoms, but, in contrast to patients with HGP, they have shorter telomeres, a higher degree of genetic instability, and a high cancer rate.…”

An Update of Molecular Basis of Telomere Biology Diseases

“…Telomere length was reduced in homozygous and heterozygotes older than 30 years patients, in accordance with the respective cancer rates. [119]. Unresolved DNA recombination and/or replication intermediates persist into mitosis, leading to chromosome segregation defects and genome instability that most likely explain the growth restriction seen in these subjects and in Bloom syndrome [125].…”

Diagnostic and therapeutic approach to children with Nijmegen breakage syndrome in relation to development of lymphoid malignancies

“…Alternatively, cultivated lymphoblastoid cells derived from NBS patients with long survival times (>12 years) display shorter telomeres and lower caspase 7 activities, compared to cells derived from patients with short survival times (<3 years), suggesting low apoptosis rates and increased senescence rates with effective tumour suppression. In view of the bifunctional role of telomere attrition, an unambiguous role in carcinogenesis is difficult to identify [25].…”