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J. Biol. Chem., Vol. 276, Issue 20, 16848-16856, May 18, 2001
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From the Departments of The Ku antigen (70- and 80-kDa
subunits) is a regulatory subunit of DNA-dependent
protein kinase (DNA-PK) that promotes the recruitment of the catalytic
subunit of DNA-PK (DNA-PKcs) to DNA ends and to
specific DNA sequences from which the kinase is activated. Ku and
DNA-PKcs plays essential roles in double-stranded
DNA break repair and V(D)J recombination and have been implicated in
the regulation of specific gene transcription. In a yeast two-hybrid screen of a Jurkat T cell cDNA library, we have identified a
specific interaction between the 70-kDa subunit of Ku heterodimer and
the homeodomain of HOXC4, a homeodomain protein expressed in the
hematopoietic system. Unexpectedly, a similar interaction with Ku was
observed for several additional homeodomain proteins including octamer transcription factors 1 and 2 and Dlx2, suggesting that specific binding to Ku may be a property shared by many homeodomain proteins. Ku-homeodomain binding was mediated through the extreme C terminus of
Ku70 and was abrogated by amino acid substitutions at
Lys595/Lys596. Ku binding allowed the
recruitment of the homeodomain to DNA ends and dramatically enhanced
the phosphorylation of homeodomain-containing proteins by DNA-PK. These
results suggest that Ku functions as a substrate docking protein for
signaling by DNA-PK to homeodomain proteins from DNA ends.
The Binding of Ku Antigen to Homeodomain Proteins Promotes Their
Phosphorylation by DNA-dependent Protein Kinase*
§,,,,¶,, and
**
Medicine, ¶ Cellular and
Molecular Medicine, and Biochemistry, Microbiology and
Immunology, The Loeb Health Research Institute at the Ottawa Hospital,
University of Ottawa, Ottawa, Ontario K1Y 4E9, Canada
*
This work was supported by an operating grant from the
Arthritis Society of Canada (to R. J. G. H.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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