Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation (original) (raw)

• Letter
• Published: 01 September 2000
• Sandy Chang1,3,
• Sarah R. Weiler1,
• Shridar Ganesan2,
• Jayanta Chaudhuri4,
• Chengming Zhu4,
• Steven E. Artandi1,
• Karl Lenhard Rudolph1,
• Geoffrey J. Gottlieb7,
• Lynda Chin1,5,
• Frederick W. Alt4,8 &
• …
• Ronald A. DePinho1,6

Nature Genetics volume 26, pages 85–88 (2000)Cite this article

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Abstract

Telomeres are specialized nucleoprotein complexes that serve as protective caps of linear eukaryotic chromosomes. Loss of telomere function is associated with rampant genetic instability and loss of cellular viability and renewal potential. The telomere also participates in processes of chromosomal repair, as evidenced by the ‘capture’ or de novo synthesis of telomere repeats at double-stranded breaks1,2,3,4 and by the capacity of yeast telomeres to serve as repositories of essential components of the DNA repair machinery, particularly those involved in non-homologous end-joining5,6,7 (NHEJ). Here we used the telomerase-deficient mouse, null for the essential telomerase RNA gene (Terc), to assess the role of telomerase and telomere function on the cellular and organismal response to ionizing radiation. Although the loss of telomerase activity per se had no discernable impact on the response to ionizing radiation, the emergence of telomere dysfunction in late-generation _Terc_−/− mice imparted a radiosensitivity syndrome associated with accelerated mortality. On the cellular level, the gastrointestinal crypt stem cells and primary thymocytes showed increased rates of apoptosis, and mouse embryonic fibroblasts (MEFs) showed diminished dose-dependent clonogenic survival. The radiosensitivity of telomere dysfunctional cells correlated with delayed DNA break repair kinetics, persistent chromosomal breaks and cytogenetic profiles characterized by complex chromosomal aberrations and massive fragmentation. Our findings establish a intimate relationship between functionally intact telomeres and the genomic, cellular and organismal response to ionizing radiation.

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Acknowledgements

We thank D. Livingston's laboratory for advice on the double-strand DNA break repair assay; W. Swat for advice on the thymocyte assays; and J. Sekiguchi, K. Mills, Y. Gu and D. Fergueson for critically reading the manuscript. This work was supported by grants from the National Institutes of Health (R01HD34880, R01HD28317). K.L.R. is supported by a grant of the Deutsche Forschungsgemeinschaft (Ru 745/1-1). F.W.A. is an Investigator of the Howard Hughes Medical Institute. L.C. is supported by grant from the National Institutes of Health (K08AR02104-01) and is a foundation scholar. S.E.A., K.K.W., S.C. and S.G. are Howard Hughes Physican Postdoctoral fellows. C.Z. is a Cancer Research Institute Fellow. J.C. is a Walter Winchell Damon Runyon Cancer Research fellow. Support from the DFCI/HCC Cancer Core grant to R.A.D. and L.C. is acknowledged. R.A.D. is an American Cancer Society Research Professor.

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Authors and Affiliations

1. Department of Adult Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
   Kwok-Kin Wong, Sandy Chang, Sarah R. Weiler, Steven E. Artandi, Karl Lenhard Rudolph, Lynda Chin & Ronald A. DePinho
2. Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
   Shridar Ganesan
3. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA
   Sandy Chang
4. The Center for Blood Research and Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA
   Jayanta Chaudhuri, Chengming Zhu & Frederick W. Alt
5. Department of Dermatology, Harvard Medical School, Boston, Massachusetts, USA
   Lynda Chin
6. Department of Genetics and Medicine, Harvard Medical School, Boston, Massachusetts, USA
   Ronald A. DePinho
7. Quest Diagnostics, Inc., Anatomical Pathology, Teterboro, New Jersey, USA
   Geoffrey J. Gottlieb
8. Howard Hughes Medical Institute, Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
   Frederick W. Alt

Authors

1. Kwok-Kin Wong
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2. Sandy Chang
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3. Sarah R. Weiler
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4. Shridar Ganesan
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5. Jayanta Chaudhuri
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6. Chengming Zhu
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7. Steven E. Artandi
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8. Karl Lenhard Rudolph
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9. Geoffrey J. Gottlieb
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10. Lynda Chin
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11. Frederick W. Alt
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12. Ronald A. DePinho
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Correspondence toRonald A. DePinho.

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Wong, KK., Chang, S., Weiler, S. et al. Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation.Nat Genet 26, 85–88 (2000). https://doi.org/10.1038/79232

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• Received: 20 April 2000
• Accepted: 23 May 2000
• Issue Date: 01 September 2000
• DOI: https://doi.org/10.1038/79232

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