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Published online April 16, 2007
doi:10.1083/jcb.200608077
The Journal of Cell Biology, Vol. 177, No. 2, 219-229
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Uematsu et al.
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Article

Autophosphorylation of DNA-PKCS regulates its dynamics at DNA double-strand breaks



Naoya Uematsu1, Eric Weterings1, Ken-ichi Yano1, Keiko Morotomi-Yano1, Burkhard Jakob2, Gisela Taucher-Scholz2, Pierre-Olivier Mari3, Dik C. van Gent3, Benjamin P.C. Chen1, and David J. Chen1

1 Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390
2 Gesellschaft für Schwerionenforschung, Biophysik, D-64291 Darmstadt, Germany
3 Department of Cell Biology and Genetics, Erasmus Medical Center, University Medical Center, 3000 CA Rotterdam, Netherlands

Correspondence to David J. Chen: david.chen{at}utsouthwestern.edu

The DNA-dependent protein kinase catalytic subunit (DNA-PKCS) plays an important role during the repair of DNA double-strand breaks (DSBs). It is recruited to DNA ends in the early stages of the nonhomologous end-joining (NHEJ) process, which mediates DSB repair. To study DNA-PKCS recruitment in vivo, we used a laser system to introduce DSBs in a specified region of the cell nucleus. We show that DNA-PKCS accumulates at DSB sites in a Ku80-dependent manner, and that neither the kinase activity nor the phosphorylation status of DNA-PKCS influences its initial accumulation. However, impairment of both of these functions results in deficient DSB repair and the maintained presence of DNA-PKCS at unrepaired DSBs. The use of photobleaching techniques allowed us to determine that the kinase activity and phosphorylation status of DNA-PKCS influence the stability of its binding to DNA ends. We suggest a model in which DNA-PKCS phosphorylation/autophosphorylation facilitates NHEJ by destabilizing the interaction of DNA-PKCS with the DNA ends.

N. Uematsu and E. Weterings contributed equally to this paper.

Abbreviations used in this paper: DNA-PK, DNA-dependent protein kinase; DNA-PKCS, DNA-PK catalytic subunit; DSB, double-strand break; IR, ionizing radiation; NHEJ, nonhomologous end-joining; WT, wild-type.


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