Abstract:
:The catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs) is a member of a sub-family of phosphatidylinositol (PI) 3-kinases termed PIK-related kinases. A distinguishing feature of this sub-family is the presence of a conserved C-terminal region downstream of a PI 3-kinase domain. Mutants defective in DNA-PKcs are sensitive to ionising radiation and are unable to carry out V(D)J recombination. Irs-20 is a DNA-PKcs-defective cell line with milder gamma-ray sensitivity than two previously characterised mutants, V-3 and mouse scid cells. Here we show that the DNA-PKcs protein from irs-20 cells can bind to DNA but is unable to function as a protein kinase. To verify the defect in irs-20 cells and provide insight into the function and expression of DNA-PKcs in double-strand break repair and V(D)J recombination we introduced YACs encoding human and mouse DNA-PKcs into defective mutants and achieved complementation of the defective phenotypes. Furthermore, in irs-20 we identified a mutation in DNA-PKcs that causes substitution of a lysine for a glutamic acid in the fourth residue from the C-terminus. This represents a strong candidate for the inactivating mutation and provides supportive evidence that the extreme C-terminal motif is important for protein kinase activity.
journal_name
Nucleic Acids Resjournal_title
Nucleic acids researchauthors
Priestley A,Beamish HJ,Gell D,Amatucci AG,Muhlmann-Diaz MC,Singleton BK,Smith GC,Blunt T,Schalkwyk LC,Bedford JS,Jackson SP,Jeggo PA,Taccioli GEdoi
10.1093/nar/26.8.1965subject
Has Abstractpub_date
1998-04-15 00:00:00pages
1965-73issue
8eissn
0305-1048issn
1362-4962pii
gkb334journal_volume
26pub_type
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