Accelerated telomere shortening in ataxia telangiectasia

Metcalfe, Judith A.; Parkhill, Julian; Campbell, Louise J.; Stacey, Michael W.; Biggs, Paul; Byrd, P. J.; Taylor, Alexander M.

doi:10.1038/ng0796-350

Cited by 315 publications

(203 citation statements)

References 22 publications

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“…One mechanism to explain these observations is suggested by the accelerated senescence typical of AT cells (Lavin and Shiloh, 1997;Vaziri et al, 1997) and by the role of telomeres. In a cell, the length of telomeres is presumably regulated by the number of divisions it has undergone (Harley et al, 1990), and abnormal telomere maintenance (accelerated telomere shortening) exists in AT cells (Xia et al, 1996;Metcalfe et al, 1996;Pandita et al, 1995;Vaziri et al, 1997). Thus if ATM has a role both in telomere maintenance (as suggested by a recent report (Smilenov et al, 1997)) as well as in DNA damage signalling, one might speculate that in fact both processes use the same machinery.…”

Section: Discussionmentioning

confidence: 99%

The ATM protein is required for sustained activation of NF-κB following DNA damage

1999

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Cells lacking an intact ATM gene are hypersensitive to ionizing radiation and show multiple defects in the cell cycle-coupled checkpoints. DNA damage usually triggers cell cycle arrest through, among other things, the activation of p53. Another DNA-damage responsive factor is NF-kB. It is activated by various stress situations, including oxidative stress, and by DNAdamaging compounds such as topoisomerase poisons. We found that cells from Ataxia Telangiectasia patients exhibit a defect in NF-kB activation in response to treatment with camptothecin, a topoisomerase I poison. In AT cells, this activation is shortened or suppressed, compared to that observed in normal cells. Ectopic expression of the ATM protein in AT cells increases the activation of NF-kB in response to camptothecin. MO59J glioblastoma cells that do not express the DNA-PK catalytic subunit respond normally to camptothecin. These results support the hypothesis that NFkB is a DNA damage-responsive transcription factor and that its activation pathway by DNA damage shares some components with the one leading to p53 activation.

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Section: Discussionmentioning

confidence: 99%

The ATM protein is required for sustained activation of NF-κB following DNA damage

1999

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“…In ataxia-telangiectasia, a progeric immunodeficiency disorder, telomere attrition is caused by the defects in genetic mechanisms that ensure telomere maintenance [22]. A cause of accelerated telomere shortening in lymphocytes, independent on genetic background, is chronic stimulation by infectious agents, as for example cytomegalovirus [20], HCV [23] or HIV [24] infection.…”

Section: Discussionmentioning

confidence: 99%

Telomere‐dependent replicative senescence of B and T cells from patients with type 1a common variable immunodeficiency

et al. 2011

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A subset of patients with common variable immunodeficiency (CVID), group 1a of the Freiburg classification, is characterized by increased B cells expressing low levels of CD21 (CD21 low ), lymphoproliferation and autoimmunity. The CD21 low B cells have been shown to be profoundly anergic, and defects of BCR-mediated calcium signaling and of T cells have been described in CVID 1a. We found that also the classical naïve B cells from CVID 1a patients, but not from CVID non-1a patients, proliferated poorly. The B cells of CVID 1a patients had a reduced capacity to divide reminiscent of the proliferative arrest associated with replicative senescence. Thus, we investigated whether lymphocyte dysfunction in CVID 1a was related to telomere-dependent replicative senescence, and found that both the B and the T cells from CVID 1a patients had significantly shorter telomeres compared with B and T cells from CVID non-1a patients. Telomere lengths in B and T cells were significantly correlated, indicating that the rate of telomere attrition in lymphocytes is an individual characteristic of CVID patients. Our findings suggest that telomere-dependent replicative senescence contributes to the immune dysfunction of CVID 1a patients, and may provide an important clue for a better understanding of the pathogenesis of CVID.Key words: Anergy . IntroductionCommon variable immunodeficiency (CVID) is a heterogeneous disorder characterized by reduced antibody levels with low to normal numbers of circulating B cells [1]. Only a small proportion of CVID patients can be classified by the underlying genetic defect [2], and current classifications are mainly based on the B-cell phenotype [3,4]. A subset of CVID is hallmarked by the expansion of an unusual population of B cells with reduced expression of CD21 (CD21 low ); these patients are classified as CVID group 1a according to the Freiburg study [3]. Clinically, CVID 1a is characterized by a late onset, autoimmunity and benign polyclonal lymphoproliferation [3,4]. In addition, several T-cell abnormalities have been described in CVID 1a patients [5]. 854The CD21 low B cells of CVID patients express an array of inhibitory receptor and fail to proliferate in response to BCRdependent and -independent stimuli [6,7]. However, anergy is not limited to CD21 low B cells, since all mature B cells from CVID 1a patients fail to flux calcium upon BCR triggering [8]. CD21 low B cells are also increased in patients with HIV infection [9], systemic lupus erythematosus [10], or mixed cryoglobulinemia secondary to HCV infection [11,12], all conditions characterized by B-cell hyperactivation. Although the CD21 low B cells of patients with HIV infection or HCV-associated mixed cryoglobulinemia have mutated immunoglobulin genes [10][11][12], the CD21 low B cells of CVID 1a patients are unmutated and mostly autoreactive [6,7]. Similarly to those of patients with CVID, the CD21 low B cells of patients with HIV infection are profoundly anergic to B-cell stimuli [9].In this study, we observed that the B cells fr...

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“…Accelerated telomere shortening, and high frequency of telomeric fusions in A-T cells Metcalfe et al, 1996;Xia et al, 1996) indicate an important role for ATM in telomere metabolism. Alterations in the nucleosomal periodicity of telomere chromatin and in its interaction with the nuclear matrix were recently observed in A-T cells (Smilenov et al, 1999).…”

Section: Dsb Repair and Chromatin Alterationsmentioning

confidence: 99%

ATM: A mediator of multiple responses to genotoxic stress

1999

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The ATM protein kinase is the product of the gene responsible for the pleiotropic recessive disorder ataxiatelangiectasia. ATM-de®cient cells show enhanced sensitivity and greatly reduced responses to genotoxic agents that generate DNA double strand breaks (DSBs), such as ionizing radiation and radiomimetic chemicals, but exhibit normal responses to DNA adducts and base modi®cations induced by other agents. Therefore, DSBs are most likely the predominant signal for the activation of ATM-mediated pathways. Identi®cation of the ATM gene triggered extensive research aimed at elucidating the numerous functions of its large multifaceted protein product. While ATM has both nuclear and cytoplasmic functions, this review will focus on its roles in the nucleus where it plays a central role in the very early stages of damage detection and serves as a master controller of cellular responses to DSBs. By activating key regulators of multiple signal transduction pathways, ATM mediates the e cient induction of a signaling network responsible for repair of the damage, and for cellular recovery and survival.

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Accelerated telomere shortening in ataxia telangiectasia

Cited by 315 publications

References 22 publications

The ATM protein is required for sustained activation of NF-κB following DNA damage

The ATM protein is required for sustained activation of NF-κB following DNA damage

Telomere‐dependent replicative senescence of B and T cells from patients with type 1a common variable immunodeficiency

ATM: A mediator of multiple responses to genotoxic stress

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