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Molecular and Cellular Biology, January 2004, p. 899-911, Vol. 24, No. 2
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.2.899-911.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Genomic Instability and Enhanced Radiosensitivity in Hsp70.1- and Hsp70.3-Deficient Mice

Clayton R. Hunt,1 David J. Dix,2 Girdhar G. Sharma,1 Raj K. Pandita,1 Arun Gupta,1 Margo Funk,1 and Tej K. Pandita1*

Department of Oncology, Radiation, Washington University School of Medicine, St. Louis, Missouri 63108,1 Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 277112

Received 22 August 2003/ Returned for modification 23 September 2003/ Accepted 15 October 2003

Heat shock proteins (HSPs) are highly conserved among all organisms from prokaryotes to eukaryotes. In mice, the HSP genes Hsp70.1 and Hsp70.3 are induced by both endogenous and exogenous stressors, such as heat and toxicants. In order to determine whether such proteins specifically influence genomic instability, mice deficient for Hsp70.1 and Hsp70.3 (Hsp70.1/3-/- mice) were generated by gene targeting. Mouse embryonic fibroblasts (MEFs) prepared from Hsp70.1/3-/- mice did not synthesize Hsp70.1 or Hsp70.3 after heat-induced stress. While the Hsp70.1/3-/- mutant mice were fertile, their cells displayed genomic instability that was enhanced by heat treatment. Cells from Hsp70.1/3-/- mice also display a higher frequency of chromosome end-to-end associations than do control Hsp70.1/3+/+ cells. To determine whether observed genomic instability was related to defective chromosome repair, Hsp70.1/3-/- and Hsp70.1/3+/+ fibroblasts were treated with ionizing radiation (IR) alone or heat and IR. Exposure to IR led to more residual chromosome aberrations, radioresistant DNA synthesis (a hallmark of genomic instability), increased cell killing, and enhanced IR-induced oncogenic transformation in Hsp70.1/3-/- cells. Heat treatment prior to IR exposure enhanced cell killing, S-phase-specific chromosome damage, and the frequency of transformants in Hsp70.1/3-/- cells in comparison to Hsp70.1/3+/+ cells. Both in vivo and in vitro studies demonstrate for the first time that Hsp70.1 and Hsp70.3 have an essential role in maintaining genomic stability under stress conditions.

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

Molecular and Cellular Biology, January 2004, p. 899-911, Vol. 24, No. 2
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.2.899-911.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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