Abstract
Ataxia-telangiectasia (A-T) results from the loss of ataxia-telangiectasia mutated (Atm) function and is characterized by accelerated telomere loss, genomic instability, progressive neurological degeneration, premature ageing and increased neoplasia incidence1. Here we evaluate the functional interaction of Atm and telomeres in vivo. We examined the impact of Atm deficiency as a function of progressive telomere attrition at both the cellular and whole-organism level in mice doubly null for Atm and the telomerase RNA component (Terc)2,3,4. These compound mutants showed increased telomere erosion and genomic instability, yet they experienced a substantial elimination of T-cell lymphomas associated with Atm deficiency. A generalized proliferation defect was evident in all cell types and tissues examined, and this defect extended to tissue stem/progenitor cell compartments, thereby providing a basis for progressive multi-organ system compromise, accelerated ageing and premature death. We show that Atm deficiency and telomere dysfunction act together to impair cellular and whole-organism viability, thus supporting the view that aspects of A-T pathophysiology are linked to the functional state of telomeres and its adverse effects on stem/progenitor cell reserves.
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Acknowledgements
We thank D. Castrillon and M. Bosenberg for advice on histo-pathological analyses, and S. Weiler, D. Castrillon, N. Sharpless, N. Bardeesy, C. Khoo and S. Chang for critical reading of the manuscript. K.-K.W. is a Howard Hughes Physician Postdoctoral Fellow. R.S.M. is supported by a Damon Runyon Cancer Research Fund Fellowship. R.M.B. and D.R.C. are both NIH Mentored Clinician Scientists awardees. F.W.A. is supported by the Howard Hughes Medical Institute. This work was supported by grants from the NIH and ACS to R.A.D. R.A.D. is an American Cancer Society Research Professor and a Steven and Michele Kirsch Investigator.
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41586_2003_BFnature01385_MOESM3_ESM.jpg
Supplementary figure 2. Representative telomere-FISH metaphases spreads from G4 mTerc-/- Atm+/+ and G4 mTerc-/- Atm-/- primary bone marrow culture and representative H&E stains of the bone marrow from the respective mice (JPG 67 kb)
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Wong, KK., Maser, R., Bachoo, R. et al. Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 421, 643–648 (2003). https://doi.org/10.1038/nature01385
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DOI: https://doi.org/10.1038/nature01385
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