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J. Biol. Chem., Vol. 282, Issue 14, 10605-10613, April 6, 2007

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Loading of the Nonhomologous End Joining Factor, Ku, on Protein-occluded DNA Ends^*

From the Lineberger Comprehensive Cancer Center and Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599

The nonhomologous end joining pathway for DNA double strand break repair requires Ku to bind DNA ends and subsequently recruit other nonhomologous end joining factors, including the DNA-dependent protein kinase catalytic subunit and the XRCC4-Ligase IV complex, to the break site. Ku loads at a break by threading the DNA ends through a circular channel in its structure. This binding mechanism explains both the high specificity of Ku for ends and its ability to translocate along DNA once loaded. However, DNA in cells is typically coated with other proteins (e.g. histones), which might be expected to block the ability of Ku to load in this manner. Here we address how the nature of a protein obstruction dictates how Ku interacts with a DNA end. Ku is unable to access the ends within an important intermediate in V(D)J recombination (a complex of RAG proteins bound to cleaved recombination targeting signals), but Ku readily displaces the linker histone, H1, from DNA. Ku also retains physiological affinity for nucleosome-associated ends. Loading onto nucleosome-associated ends still occurs by threading the end through its channel, but rather than displacing the nucleosome, Ku peels as much as 50 bp of DNA away from the histone octamer surface. We suggest a model where Ku utilizes an unusual characteristic of its three-dimensional structure to recognize certain protein-occluded ends without the extensive remodeling of chromatin structure required by other DNA repair pathways.

Received for publication, December 4, 2006 , and in revised form, February 6, 2007.

^* This work was supported by United States Public Health Service Grant CA-84442 (to D. A. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ A Leukemia and Lymphoma Society Scholar. To whom correspondence should be addressed: Lineberger Comprehensive Cancer Center and Dept. of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, CB-7295, Chapel Hill, NC 27599. Tel.: 919-966-9839; Fax: 919-966-3015; E-mail: dale_ramsden{at}med.unc.edu.

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