Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing.

Authors: Wong KK; Maser RS; Bachoo RM; Menon J; Carrasco DR; Gu Y; Alt FW; DePinho RA

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 incidence. 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). 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.

Keywords: Aging/*genetics; Alopecia/genetics; Anaphase; Animals; Apoptosis; Cell Cycle Proteins; Cell Division; Cells, Cultured; DNA-Binding Proteins; Fibroblasts; Hair Color/genetics; Homeostasis/*genetics; Lymphoma, T-Cell/genetics; Mice; Mice, Knockout; Protein-Serine-Threonine Kinases/deficiency/*genetics; RNA/*genetics; Stem Cells/cytology/metabolism; Survival Rate; Telomerase/*genetics; Telomere/enzymology/genetics/*metabolism; Tumor Suppressor Protein p53/metabolism; Tumor Suppressor Proteins; Wound Healing/genetics
Journal: Nature
Volume: 421
Issue: 6923
Pages: 643-8
Date: Jan. 24, 2003
PMID: 12540856
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Wong KK, Maser RS, Bachoo RM, Menon J, Carrasco DR, Gu Y, Alt FW, DePinho RA (2003) Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 421: 643-8.

Study Lifespan Factors:
  • Atm Ataxia telangiectasia mutated homolog (human)

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