Autophosphorylation of DNA-PKCS regulates its dynamics at DNA double-strand breaks |
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Authors: | Uematsu Naoya Weterings Eric Yano Ken-ichi Morotomi-Yano Keiko Jakob Burkhard Taucher-Scholz Gisela Mari Pierre-Olivier van Gent Dik C Chen Benjamin P C Chen David J |
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Institution: | Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. |
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Abstract: | The DNA-dependent protein kinase catalytic subunit (DNA-PK(CS)) 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-PK(CS) recruitment in vivo, we used a laser system to introduce DSBs in a specified region of the cell nucleus. We show that DNA-PK(CS) accumulates at DSB sites in a Ku80-dependent manner, and that neither the kinase activity nor the phosphorylation status of DNA-PK(CS) influences its initial accumulation. However, impairment of both of these functions results in deficient DSB repair and the maintained presence of DNA-PK(CS) at unrepaired DSBs. The use of photobleaching techniques allowed us to determine that the kinase activity and phosphorylation status of DNA-PK(CS) influence the stability of its binding to DNA ends. We suggest a model in which DNA-PK(CS) phosphorylation/autophosphorylation facilitates NHEJ by destabilizing the interaction of DNA-PK(CS) with the DNA ends. |
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