MDC1 regulates DNA-PK autophosphorylation in response to DNA damage

被引:65
作者
Lou, ZK
Chen, BPC
Asaithamby, A
Minter-Dykhouse, K
Chen, DJ
Chen, JJ
机构
[1] Mayo Clin & Mayo Fdn, Dept Oncol, Rochester, MN 55905 USA
[2] Univ Calif Berkeley, Lawrence Berkeley Lab, Div Life Sci, Berkeley, CA 94720 USA
关键词
D O I
10.1074/jbc.C400375200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
DNA damage initiates signaling events through kinase cascades that result in cell cycle checkpoint control and DNA repair. However, it is not yet clear how the signaling pathways relay to DNA damage repair. Using the repeat region of checkpoint protein MDC1 (mediator of DNA damage checkpoint protein 1), we identified DNA-PKcs/Ku as MDC1-associated proteins. Here, we show that MDC1 directly interacts with the Ku/DNA-PKcs complex. Down-regulation of MDC1 resulted in defective phospho-DNA-PKcs foci formation and DNA-PKcs autophosphorylation, suggesting that MDC1 regulates autophosphorylation of DNA-PKcs following DNA damage. Furthermore, DNA-PK-dependent DNA damage repair is defective in cells depleted of MDC1. Taken together, these results suggest that the MDC1 repeat region is involved in protein-protein interaction with DNA-PKcs/Ku, and MDC1 regulates DNA damage repair by influencing DNA-PK autophosphorylation. Therefore, MDC1 acts not only as a mediator of DNA damage checkpoint but also as a mediator of DNA damage repair.
引用
收藏
页码:46359 / 46362
页数:4
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