Document Detail

The N-terminal region of the DNA-dependent protein kinase catalytic subunit is required for its DNA double-stranded break-mediated activation.
MedLine Citation:
PMID:  23322783     Owner:  NLM     Status:  MEDLINE    
DNA-dependent protein kinase (DNA-PK) plays an essential role in the repair of DNA double-stranded breaks (DSBs) mediated by the nonhomologous end-joining pathway. DNA-PK is a holoenzyme consisting of a DNA-binding (Ku70/Ku80) and catalytic (DNA-PKcs) subunit. DNA-PKcs is a serine/threonine protein kinase that is recruited to DSBs via Ku70/80 and is activated once the kinase is bound to the DSB ends. In this study, two large, distinct fragments of DNA-PKcs, consisting of the N terminus (amino acids 1-2713), termed N-PKcs, and the C terminus (amino acids 2714-4128), termed C-PKcs, were produced to determine the role of each terminal region in regulating the activity of DNA-PKcs. N-PKcs but not C-PKcs interacts with the Ku-DNA complex and is required for the ability of DNA-PKcs to localize to DSBs. C-PKcs has increased basal kinase activity compared with DNA-PKcs, suggesting that the N-terminal region of DNA-PKcs keeps basal activity low. The kinase activity of C-PKcs is not stimulated by Ku70/80 and DNA, further supporting that the N-terminal region is required for binding to the Ku-DNA complex and full activation of kinase activity. Collectively, the results show the N-terminal region mediates the interaction between DNA-PKcs and the Ku-DNA complex and is required for its DSB-induced enzymatic activity.
Anthony J Davis; Kyung-Jong Lee; David J Chen
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-15
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  288     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-11     Completed Date:  2013-04-30     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  7037-46     Citation Subset:  IM    
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MeSH Terms
Antigens, Nuclear / chemistry,  genetics,  metabolism
Blotting, Western
CHO Cells
DNA / genetics,  metabolism
DNA Breaks, Double-Stranded*
DNA Repair*
DNA-Activated Protein Kinase / chemistry,  genetics,  metabolism*
DNA-Binding Proteins / chemistry,  genetics,  metabolism
Enzyme Activation
HeLa Cells
Luminescent Proteins / genetics,  metabolism
Nuclear Proteins / chemistry,  genetics,  metabolism*
Peptide Fragments / chemistry,  metabolism
Protein Binding
Protein Multimerization
Sf9 Cells
Grant Support
CA092584/CA/NCI NIH HHS; CA134991/CA/NCI NIH HHS; CA162804/CA/NCI NIH HHS; P01 CA092584/CA/NCI NIH HHS; R01 CA050519/CA/NCI NIH HHS; R01 CA134991/CA/NCI NIH HHS; R01 CA162804/CA/NCI NIH HHS; R37 CA050519/CA/NCI NIH HHS
Reg. No./Substance:
0/Antigens, Nuclear; 0/DNA-Binding Proteins; 0/Ku autoantigen; 0/Luminescent Proteins; 0/Nuclear Proteins; 0/Peptide Fragments; 9007-49-2/DNA; EC Protein Kinase; EC protein, human
Erratum In:
J Biol Chem. 2013 Jun 28;288(26):18776

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