Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing (original) (raw)
- Letter
- Published: 22 January 2003
- Richard S. Maser1,6,
- Robert M. Bachoo1,5,
- Jayant Menon7,
- Daniel R. Carrasco1,4,
- Yansong Gu8,
- Frederick W. Alt3,2 &
- …
- Ronald A. DePinho1,6
Nature volume 421, pages 643–648 (2003)Cite this article
- 2397 Accesses
- 321 Citations
- 9 Altmetric
- Metrics details
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Additional access options:
Similar content being viewed by others
References
- Shiloh, Y. & Kastan, M. B. ATM: genome stability, neuronal development, and cancer cross paths. Adv. Cancer Res. 83, 209–254 (2001)
Article CAS Google Scholar - Lee, H. W. et al. Essential role of mouse telomerase in highly proliferative organs. Nature 392, 569–574 (1998)
Article ADS CAS Google Scholar - Blasco, M. A. et al. Telomere shortening and tumour formation by mouse cells lacking telomerase RNA. Cell 91, 25–34 (1997)
Article CAS Google Scholar - Borghesani, P. R. et al. Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice. Proc. Natl Acad. Sci. USA 97, 3336–3341 (2000)
Article ADS CAS Google Scholar - Kastan, M. B. & Lim, D. S. The many substrates and functions of ATM. Nature Rev. Mol. Cell Biol. 1, 179–186 (2000)
Article CAS Google Scholar - Metcalfe, J. A. et al. Accelerated telomere shortening in ataxia telangiectasia. Nature Genet. 13, 350–353 (1996)
Article CAS Google Scholar - Pandita, T. K. ATM function and telomere stability. Oncogene 21, 611–618 (2002)
Article CAS Google Scholar - Karlseder, J., Broccoli, D., Dai, Y., Hardy, S. & de Lange, T. p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. Science 283, 1321–1325 (1999)
Article CAS Google Scholar - Barlow, C. et al. Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 86, 159–171 (1996)
Article CAS Google Scholar - Elson, A. et al. Pleiotropic defects in ataxia-telangiectasia protein-deficient mice. Proc. Natl Acad. Sci. USA 93, 13084–13089 (1996)
Article ADS CAS Google Scholar - Xu, Y. et al. Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev. 10, 2411–2422 (1996)
Article CAS Google Scholar - Kipling, D. & Cooke, H. J. Hypervariable ultra-long telomeres in mice. Nature 347, 400–402 (1990)
Article ADS CAS Google Scholar - Chin, L. et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97, 527–538 (1999)
Article CAS Google Scholar - Hande, M. P., Samper, E., Lansdorp, P. & Blasco, M. A. Telomere length dynamics and chromosomal instability in cells derived from telomerase null mice. J. Cell Biol. 144, 589–601 (1999)
Article CAS Google Scholar - Vaziri, H. et al. ATM-dependent telomere loss in aging human diploid fibroblasts and DNA damage lead to the post-translational activation of p53 protein involving poly(ADP-ribose) polymerase. EMBO J. 16, 6018–6033 (1997)
Article CAS Google Scholar - Hande, M. P., Balajee, A. S., Tchirkov, A., Wynshaw-Boris, A. & Lansdorp, P. M. Extra-chromosomal telomeric DNA in cells from Atm(-/-) mice and patients with ataxia-telangiectasia. Hum. Mol. Genet. 10, 519–528 (2001)
Article CAS Google Scholar - Booth, C. & Potten, C. S. Gut instincts: thoughts on intestinal epithelial stem cells. J. Clin. Invest. 105, 1493–1499 (2000)
Article CAS Google Scholar - Reynolds, B. A. & Weiss, S. Clonal and population analyses demonstrate that an EGF-responsive mammalian embryonic CNS precursor is a stem cell. Dev. Biol. 175, 1–13 (1996)
Article CAS Google Scholar - Ahmed, S., Reynolds, B. A. & Weiss, S. BDNF enhances the differentiation but not the survival of CNS stem cell-derived neuronal precursors. J. Neurosci. 15, 5765–5778 (1995)
Article CAS Google Scholar - Altman, J. & Bayor, S. A. in Development of the Cerebellar System in Relations to its Evolution, Structure and Functions 727–750 (CRC, London, 1997)
Google Scholar - Eilam, R. et al. Selective loss of dopaminergic nigro-striatal neurons in brains of Atm- deficient mice. Proc. Natl Acad. Sci. USA 95, 12653–12656 (1998)
Article ADS CAS Google Scholar - Spector, B. D., Filipovich, A. H., Perry, G. S. & Kersey, J. H. in Ataxia-telangiectasia—A Cellular and Molecular Link Between Cancer, Neuropathology and Immune Deficiency (eds Bridges, B. A. & Harnden, D. G.) 103–138 (Wiley, New York, 1982)
Google Scholar - Rudolph, K. L. et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96, 701–712 (1999)
Article CAS Google Scholar - Artandi, S. E. et al. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 406, 641–645 (2000)
Article ADS CAS Google Scholar - Tyner, S. D. et al. p53 mutant mice that display early ageing-associated phenotypes. Nature 415, 45–53 (2002)
Article ADS CAS Google Scholar - Greenberg, R. A. et al. Short dysfunctional telomeres impair tumorigenesis in the INK4a(delta2/3) cancer-prone mouse. Cell 97, 515–525 (1999)
Article CAS Google Scholar - Smogorzewska, A. & de Lange, T. Different telomere damage signaling pathways in human and mouse cells. EMBO J. 21, 4338–4348 (2002)
Article CAS Google Scholar - Frank, K. M. et al. DNA ligase IV deficiency in mice leads to defective neurogenesis and embryonic lethality via the p53 pathway. Mol. Cell 5, 993–1002 (2000)
Article MathSciNet CAS Google Scholar - Sekiguchi, J. et al. Genetic interactions between ATM and the nonhomologous end-joining factors in genomic stability and development. Proc. Natl Acad. Sci. USA 98, 3243–3248 (2001)
Article ADS CAS Google Scholar - Wong, K. K. et al. Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation. Nature Genet. 26, 85–88 (2000)
Article CAS Google Scholar
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.
Author information
Authors and Affiliations
- Department of Adult Oncology, Dana Farber Cancer Institute, Massachusetts, 02115, Boston, USA
Kwok-Kin Wong, Richard S. Maser, Robert M. Bachoo, Daniel R. Carrasco & Ronald A. DePinho - Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, 02115, USA
Frederick W. Alt - The Center for Blood Research, Harvard Medical School, Boston, Massachusetts, 02115, USA
Frederick W. Alt - Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, 02115, USA
Daniel R. Carrasco - Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, 02115, USA
Robert M. Bachoo - Department of Genetics and Medicine, Harvard Medical School, Massachusetts, 02115, Boston, USA
Richard S. Maser & Ronald A. DePinho - University of California Los Angeles Medical School, Los Angeles, California, 92507, USA
Jayant Menon - Department of Radiation Oncology and Immunology, University of Washington School of Medicine, Seattle, Washington, 98195, USA
Yansong Gu
Authors
- Kwok-Kin Wong
You can also search for this author inPubMed Google Scholar - Richard S. Maser
You can also search for this author inPubMed Google Scholar - Robert M. Bachoo
You can also search for this author inPubMed Google Scholar - Jayant Menon
You can also search for this author inPubMed Google Scholar - Daniel R. Carrasco
You can also search for this author inPubMed Google Scholar - Yansong Gu
You can also search for this author inPubMed Google Scholar - Frederick W. Alt
You can also search for this author inPubMed Google Scholar - Ronald A. DePinho
You can also search for this author inPubMed Google Scholar
Corresponding author
Correspondence toRonald A. DePinho.
Ethics declarations
Competing interests
The authors declare that they have no competing financial interests.
Supplementary information
Rights and permissions
About this article
Cite this article
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
- Received: 15 October 2002
- Accepted: 17 December 2002
- Published: 22 January 2003
- Issue Date: 06 February 2003
- DOI: https://doi.org/10.1038/nature01385