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Molecular and Cellular Biology, March 2006, p. 1850-1864, Vol. 26, No. 5
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.5.1850-1864.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Mammalian Rad9 Plays a Role in Telomere Stability, S- and G2-Phase-Specific Cell Survival, and Homologous Recombinational Repair

Raj K. Pandita,1,{dagger} Girdhar G. Sharma,1,{dagger} Andrei Laszlo,1 Kevin M. Hopkins,2 Scott Davey,3 Mikhail Chakhparonian,4 Arun Gupta,1 Raymund J. Wellinger,4 Junran Zhang,1 Simon N. Powell,1 Joseph L. Roti Roti,1 Howard B. Lieberman,2 and Tej K. Pandita1*

Washington University School of Medicine, St. Louis, Missouri 63108,1 College of Physicians and Surgeons, Columbia University, New York, New York 10032,2 Queen's University, Kingston, Ontario K7L 3N6,3 Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada4

Received 7 November 2005/ Returned for modification 12 December 2005/ Accepted 19 December 2005

The protein products of several rad checkpoint genes of Schizosaccharomyces pombe (rad1+, rad3+, rad9+, rad17+, rad26+, and hus1+) play crucial roles in sensing changes in DNA structure, and several function in the maintenance of telomeres. When the mammalian homologue of S. pombe Rad9 was inactivated, increases in chromosome end-to-end associations and frequency of telomere loss were observed. This telomere instability correlated with enhanced S- and G2-phase-specific cell killing, delayed kinetics of {gamma}-H2AX focus appearance and disappearance, and reduced chromosomal repair after ionizing radiation (IR) exposure, suggesting that Rad9 plays a role in cell cycle phase-specific DNA damage repair. Furthermore, mammalian Rad9 interacted with Rad51, and inactivation of mammalian Rad9 also resulted in decreased homologous recombinational (HR) repair, which occurs predominantly in the S and G2 phases of the cell cycle. Together, these findings provide evidence of roles for mammalian Rad9 in telomere stability and HR repair as a mechanism for promoting cell survival after IR exposure.

* Corresponding author. Mailing address: Department of Radiation Oncology, Washington University School of Medicine, 4511 Forest Park Ave., St. Louis, MO 63108. Phone: (314) 747-5461. Fax: (314) 362-9790. E-mail: pandita{at}wustl.edu.

{dagger} R.K.P. and G.G.S. contributed equally to this work.

Molecular and Cellular Biology, March 2006, p. 1850-1864, Vol. 26, No. 5
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.5.1850-1864.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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