Carcinogenesis, Vol 19, 965-971, Copyright © 1998 by Oxford University Press
S Jin, S Inoue and DT Weaver
Etoposides block cell division by interfering with the action of
topoisomerase II, leaving enzyme-DNA double-strand breaks. We found that
certain components of the trimeric DNA-dependent protein kinase influence
cell survival following etoposide damage. Interestingly, either Ku70- or
Ku80-deficient cell lines, but not mutant cell lines of the DNA-PK
catalytic sub-unit (DNA-PKcs), were found to be hypersensitive to the
effects of etoposide VP16. Ku70- and Ku80- deficient cells can be
complemented to an etoposide resistant phenotype by introducing wildtype
Ku70 or Ku80 cDNAs. Mutational analysis of introduced Ku70 cDNAs into
murine embryonic stem cells deleted for Ku70 (-/-) showed that mutants
where heterodimerization and DNA binding functions of Ku were disrupted,
also blocked the restoration of etoposide resistance. In contrast with the
differential etoposide sensitivity of DNA-PK mutants, both Ku- and
DNA-PKcs-deficient cell lines showed G2 ionizing radiation-induced delays,
a cell cycle phase where topoisomerase II function is critical. Thus, the
topoisomerase II cleaved complexes may be an example of DNA lesions
requiring the Ku heterodimer, but not DNA-PK for DNA repair.
ARTICLES
Differential etoposide sensitivity of cells deficient in the Ku and DNA- PKcs components of the DNA-dependent protein kinase
Division of Tumor Immunology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
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