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Nucleic Acids Research Advance Access originally published online on September 6, 2008
Nucleic Acids Research 2008 36(17):5713-5726; doi:10.1093/nar/gkn572
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Nucleic Acids Research, 2008, Vol. 36, No. 17 5713-5726
© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Nucleic Acid Enzymes

Evidence for an inositol hexakisphosphate-dependent role for Ku in mammalian nonhomologous end joining that is independent of its role in the DNA-dependent protein kinase

Joyce C.Y. Cheung, Brenda Salerno and Les A. Hanakahi*

Department of Biochemistry and Molecular Biology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD 21205, USA

*To whom correspondence should be addressed. Tel: +1 443 287 2515; Fax: +1 410 955 2926; Email: lhanakah{at}jhsph.edu

Received June 7, 2008. Revised August 22, 2008. Accepted August 23, 2008.

Nonhomologous end-joining (NHEJ) is an important pathway for the repair of DNA double-strand breaks (DSBs) and plays a critical role in maintaining genomic stability in mammalian cells. While Ku70/80 (Ku) functions in NHEJ as part of the DNA-dependent protein kinase (DNA-PK), genetic evidence indicates that the role of Ku in NHEJ goes beyond its participation in DNA-PK. Inositol hexakisphosphate (IP6) was previously found to stimulate NHEJ in vitro and Ku was identified as an IP6-binding factor. Through mutational analysis, we identified a bipartite IP6-binding site in Ku and generated IP6-binding mutants that ranged from 1.22% to 58.48% of wild-type binding. Significantly, these Ku IP6-binding mutants were impaired for participation in NHEJ in vitro and we observed a positive correlation between IP6 binding and NHEJ. Ku IP6-binding mutants were separation-of-function mutants that bound DNA and activated DNA-PK as well as wild-type Ku. Our observations identify a hitherto undefined IP6-binding site in Ku and show that this interaction is important for DSB repair by NHEJ in vitro. Moreover, these data indicate that in addition to binding of exposed DNA termini and activation of DNA-PK, the Ku heterodimer plays a role in mammalian NHEJ that is regulated by binding of IP6.


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