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Mol. Cell. Biol. doi:10.1128/MCB.02366-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Trans autophosphorylation at DNA-PK's two major autophosphorylation site clusters facilitates end processing but not end joining

College of Veterinary Medicine and Department of Pathobiology and Diagnostic Investigation, Michigan State University; East Lansing, Michigan 48824; Departments of Biochemistry & Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, Canada T2N4N1

^* To whom correspondence should be addressed. Email: kmeek{at}msu.edu.

	Abstract

Recent studies have established that DNA-PK undergoes a series of autophosphorylation events that facilitate successful completion of non-homologous DNA end joining. Autophosphorylation at sites in two distinct clusters regulates DNA end access to DNA end processing factors and to other DNA repair pathways. Autophosphorylation within the kinase's activation loop regulates kinase activity. Additional autophosphorylation events (as yet undefined) occur that mediate kinase dissociation. Here we provide the first evidence that autophosphorylation within the two major clusters (regulating end access) occurs in trans. Further, both UV induced and DSB induced phosphorylation in the two major clusters is predominately autophosphorylation. Finally, we show that while autophosphorylation in trans on one of two synapsed DNA-PK complexes facilitates appropriate end processing, this is not sufficient to promote efficient end joining. This suggests that end joining in living cells requires additional phosphorylation events that either occur in cis, or that occur on both sides of the DNA-PK synapse. These data support an emerging consensus: that via a series of autophosphorylation events, DNA-PK undergoes a sequence of conformational changes that promote efficient and appropriate repair of DSBs.

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