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Molecular and Cellular Biology, December 2005, p. 10842-10852, Vol. 25, No. 24
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.24.10842-10852.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Autophosphorylation of DNA-Dependent Protein Kinase Regulates DNA End Processing and May Also Alter Double-Strand Break Repair Pathway Choice{dagger}

Xiaoping Cui,1 Yaping Yu,2 Shikha Gupta,1 Young-Moon Cho,1 Susan P. Lees-Miller,2 and Katheryn Meek1*

College of Veterinary Medicine and Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan 48824,1 Departments of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada T2N 4N12

Received 1 August 2005/ Returned for modification 23 August 2005/ Accepted 22 September 2005

Two highly conserved double-strand break (DSB) repair pathways, homologous recombination (HR) and nonhomologous end joining (NHEJ), function in all eukaryotes. How a cell chooses which pathway to utilize is an area of active research and debate. During NHEJ, the DNA-dependent protein kinase (DNA-PK) functions as a "gatekeeper" regulating DNA end access. Here, we provide evidence that DNA-PK regulates DNA end access via its own autophosphorylation. We demonstrated previously that autophosphorylation within a major cluster of sites likely mediates a conformational change that is critical for DNA end processing. Furthermore, blocking autophosphorylation at these sites inhibits a cell's ability to utilize the other major double-strand break repair pathway, HR. Here, we define a second major cluster of DNA-PK catalytic subunit autophosphorylation sites. Whereas blocking phosphorylation at the first cluster inhibits both end processing and HR, blocking phosphorylation at the second cluster enhances both. We conclude that separate DNA-PK autophosphorylation events may function reciprocally by not only regulating DNA end processing but also affecting DSB repair pathway choice.

* Corresponding author. Mailing address: Michigan State University, 350 FST, East Lansing, MI 48824. Phone: (517) 432-9505. Fax: (517) 353-9004. E-mail: kmeek{at}msu.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, December 2005, p. 10842-10852, Vol. 25, No. 24
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.24.10842-10852.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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