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Molecular and Cellular Biology, June 1999, p. 4065-4078, Vol. 19, No. 6
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Ku Antigen-DNA Conformation Determines the Activation of DNA-Dependent Protein Kinase and DNA Sequence-Directed Repression of Mouse Mammary Tumor Virus Transcription

Ward Giffin,1 Wenrong Gong,1 Caroline Schild-Poulter,1 and Robert J. G. Haché1,2,*

Departments of Medicine1 and Biochemistry, Microbiology and Immunology,2 The Loeb Health Research Institute at the Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada

Received 30 September 1998/Returned for modification 5 February 1999/Accepted 15 March 1999

Mouse mammary tumor virus (MMTV) transcription is repressed by DNA-dependent protein kinase (DNA-PK) through a DNA sequence element, NRE1, in the viral long terminal repeat that is a sequence-specific DNA binding site for the Ku antigen subunit of the kinase. While Ku is an essential component of the active kinase, how the catalytic subunit of DNA-PK (DNA-PKcs) is regulated through its association with Ku is only beginning to be understood. We report that activation of DNA-PKcs and the repression of MMTV transcription from NRE1 are dependent upon Ku conformation, the manipulation of DNA structure by Ku, and the contact of Ku80 with DNA. Truncation of one copy of the overlapping direct repeat that comprises NRE1 abrogated the repression of MMTV transcription by Ku-DNA-PKcs. Remarkably, the truncated element was recognized by Ku-DNA-PKcs with affinity similar to that of the full-length element but was unable to promote the activation of DNA-PKcs. Analysis of Ku-DNA-PKcs interactions with DNA ends, double- and single-stranded forms of NRE1, and the truncated NRE1 element revealed striking differences in Ku conformation that differentially affected the recruitment of DNA-PKcs and the activation of kinase activity.

* Corresponding author. Mailing address: The Loeb Health Research Institute, 725 Parkdale Ave., Ottawa, Ontario, Canada K1Y 4K9. Phone: (613) 798-5555, ext. 6283. Fax: (613) 761-5036. E-mail: rhache{at}lri.ca.

Molecular and Cellular Biology, June 1999, p. 4065-4078, Vol. 19, No. 6
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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