MCB
Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Dhar, S.
Right arrow Articles by Pandita, T. K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dhar, S.
Right arrow Articles by Pandita, T. K.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, October 2000, p. 7764-7772, Vol. 20, No. 20
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Inactivation of 14-3-3sigma Influences Telomere Behavior and Ionizing Radiation-Induced Chromosomal Instability

Sonu Dhar,1 Jeremy A. Squire,2 M. Prakash Hande,1 Raymund J. Wellinger,3 and Tej K. Pandita1,*

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 14-3-3sigma 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 14-3-3sigma -/- 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 14-3-3sigma 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 14-3-3sigma -/- 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.

Molecular and Cellular Biology, October 2000, p. 7764-7772, Vol. 20, No. 20
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:



Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
J. Bacteriol. J. Virol. Eukaryot. Cell
Microbiol. Mol. Biol. Rev. Clin. Vaccine Immunol. All ASM Journals

Copyright © 2000 by the American Society for Microbiology. All rights reserved.