Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation
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...
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Published in | Nature genetics Vol. 26; no. 1; pp. 85 - 88 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group
01.09.2000
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Subjects | |
Online Access | Get full text |
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Summary: | 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 breaks 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-joining (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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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 |
ISSN: | 1061-4036 1546-1718 |
DOI: | 10.1038/79232 |