Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing

被引：308

作者：

Kwok-Kin Wong ^{[1
]}

Richard S. Maser ^{[1
]}

Robert M. Bachoo ^{[2
]}

Jayant Menon ^{[1
]}

Daniel R. Carrasco ^{[3
]}

Yansong Gu ^{[4
]}

Frederick W. Alt ^{[1
]}

Ronald A. DePinho ^{[5
]}

机构：

[1] Department of Adult Oncology, Dana Farber Cancer Institute, Boston

[2] Department of Genetics, Harvard Medical School, Boston

[3] Department of Neurology, Brigham and Women's Hospital, Boston

[4] Department of Pathology, Brigham and Women's Hospital, Boston

[5] Center for Blood Research, Harvard Medical School, Boston

[6] Howard Hughes Medical Institute, Harvard Medical School, Boston

[7] Univ. of California LA Med. Sch., Los Angeles

[8] Department of Radiation Oncology, Univ. of Washington Sch. of Medicine, Seattle

来源：

Nature | 2003年 / 421卷 / 6923期

基金：

美国国家卫生研究院;

关键词：

D O I：

10.1038/nature01385

中图分类号：

学科分类号：

摘要：

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.

引用

页码：643 / 648

页数：5

共 30 条

[1]

Shiloh Y., Kastan M.B., ATM genome stability, neuronal development, and cancer cross paths, Adv. Cancer Res., 83, pp. 209-254, (2001)

[2]

Lee H.W., Et al., Essential role of mouse telomerase in highly proliferative organs, Nature, 392, pp. 569-574, (1998)

[3]

Blasco M.A., Et al., Telomere shortening and tumour formation by mouse cells lacking telomerase RNA, Cell, 91, pp. 25-34, (1997)

[4]

Borghesani P.R., Et al., Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice, Proc. Natl Acad. Sci. USA, 97, pp. 3336-3341, (2000)

[5]

Kastan M.B., Lim D.S., The many substrates and functions of ATM, Nature Rev. Mol. Cell Biol., 1, pp. 179-186, (2000)

[6]

Metcalfe J.A., Et al., Accelerated telomere shortening in ataxia telangiectasia, Nature Genet., 13, pp. 350-353, (1996)

[7]

Pandita T.K., ATM function and telomere stability, Oncogene, 21, pp. 611-618, (2002)

[8]

Karlseder J., Broccoli D., Dai Y., Hardy S., De Lange T., p53- and ATM-dependent apoptosis induced by telomeres lacking TRF 2, Science, 283, pp. 1321-1325, (1999)

[9]

Barlow C., Et al., Atm-deficient mice: A paradigm of ataxia telangiectasia, Cell, 86, pp. 159-171, (1996)

[10]

Elson A., Et al., Pleiotropic defects in ataxia-telangiectasia protein-deficient mice, Proc. Natl Acad. Sci. USA, 93, pp. 13084-13089, (1996)

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