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Molecular and Cellular Biology, October 2000, p. 7764-7772, Vol. 20, No. 20
Center for Radiological Research, College of Physicians and
Surgeons, Columbia University, New York, New York
10032,1 and Department of Medical
Biophysics, University of Toronto, Ontario,2 and
Département de Microbiologie et Infectiologie,
Faculté de Médecine, Université de Sherbrooke,
Sherbrooke, Quebec J1H 5N4,3 Canada
Received 13 April 2000/Returned for modification 30 May
2000/Accepted 31 July 2000
Telomeres are complexes of repetitive DNA sequences and proteins
constituting the ends of linear eukaryotic chromosomes. While these
structures are thought to be associated with the nuclear matrix, they
appear to be released from this matrix at the time when the cells exit
from G2 and enter M phase. Checkpoints maintain the order
and fidelity of the eukaryotic cell cycle, and defects in checkpoints
contribute to genetic instability and cancer. The 14-3-3
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Inactivation of 14-3-3
Influences Telomere
Behavior and Ionizing Radiation-Induced Chromosomal
Instability
gene has
been reported to be a checkpoint control gene, since it promotes
G2 arrest following DNA damage. Here we demonstrate that
inactivation of this gene influences genome integrity and cell
survival. Analyses of chromosomes at metaphase showed frequent losses
of telomeric repeat sequences, enhanced frequencies of chromosome
end-to-end associations, and terminal nonreciprocal translocations in
14-3-3
/
cells. These phenotypes correlated with a
reduction in the amount of G-strand overhangs at the telomeres and an
altered nuclear matrix association of telomeres in these cells. Since
the p53-mediated G1 checkpoint is operative in these cells,
the chromosomal aberrations observed occurred preferentially in
G2 after irradiation with gamma rays, corroborating the
role of the 14-3-3
protein in G2/M progression. The
results also indicate that even in untreated cycling cells, occasional
chromosomal breaks or telomere-telomere fusions trigger a
G2 checkpoint arrest followed by repair of these aberrant
chromosome structures before entering M phase. Since 14-3-3
/
cells are defective in maintaining
G2 arrest, they enter M phase without repair of the
aberrant chromosome structures and undergo cell death during mitosis.
Thus, our studies provide evidence for the correlation among a
dysfunctional G2/M checkpoint control, genomic instability,
and loss of telomeres in mammalian cells.
*
Corresponding author. Mailing address: Center for
Radiological Research, College of Physicians & Surgeons, Columbia
University, VC11-213, 630 West 168th St., New York, NY 10032. Phone:
(212) 305-3911. Fax: (212) 305-3229. E-mail:
tkp1{at}columbia.edu.
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