NDLI: Cisplatin–DNA adducts inhibit translocation of the Ku subunits of DNA-PK

Content Provider	PubMed Central
Author	Turchi, John J. Henkels, Karen M. Zhou, Yun
Copyright Year	2000
Abstract	We have determined the effect of cisplatin–DNA damage on the ability of the DNA-dependent protein kinase (DNA-PK) to interact with duplex DNA molecules in vitro. The Ku DNA binding subunits of DNA-PK display a reduced ability to translocate on duplex DNA containing cisplatin–DNA adducts compared to control, undamaged duplex DNA. The decreased rates of translocation resulted in a decrease in the association of the p460 catalytic subunit of DNA-PK (DNA-PKcs) with the Ku–DNA complex. In addition to a decrease in DNA-PKcs association, the DNA-PKcs that is bound with Ku at a DNA end containing cisplatin–DNA adducts has a reduced catalytic rate compared to heterotrimeric DNA-PK assembled on undamaged DNA. The position of the cisplatin–DNA lesion from the terminus also effects kinase activation, with maximal inhibition occurring when the lesion is closer to the terminus. These results are consistent with a model for DNA-PK activation where the Ku dimer translocates away from the DNA terminus and facilitates the association of DNA-PKcs which interacts with both Ku and DNA resulting in kinase activation. The presence of cisplatin adducts decreases the ability to translocate away from the terminus and results in the formation of inactive kinase complexes at the DNA terminus. The results are discussed with respect to the ability of cisplatin to sensitize cells to DNA damage induced by ionizing radiation and the ability to repair DNA double-strand breaks.
Starting Page	4634
File Format	PDF
ISSN	13624962
e-ISSN	13624962
Journal	Nucleic Acids Research
Issue Number	23
Volume Number	28
Language	English
Publisher	Oxford University Press
Publisher Date	2000-12-01
Access Restriction	Open
Rights Holder	Oxford University Press
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Genetics

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Cisplatin–DNA adducts inhibit translocation of the Ku subunits of DNA-PK

Visualization of inositol phosphate-dependent mobility of Ku: depletion of the DNA–PK cofactor InsP6 inhibits Ku mobility

Visualization of inositol phosphate‐dependent mobility of Ku: depletion of the DNA–PK cofactor InsP6 inhibits Ku mobility

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Cisplatin–DNA adducts inhibit translocation of the Ku subunits of DNA-PK

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