Ku affects the ataxia and rad 3-related/CHK1-dependent S phase checkpoint response after camptothecin treatment

Hongyan Wang, Xiang Wang, Xiang Yang Zhou, David J. Chen, Gloria C. Li, George Iliakis, Ya Wang

Research output: Contribution to journalArticle

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Abstract

Camptothecin (CPT) that targets DNA topoisomerase I is one of the most promising broad-spectrum anticancer drugs in development today. The cytotoxicity of CPT is S phase (S)-specific because the collision of advancing replication forks with CPT-topoisomerase I-DNA complexes results in DNA damage. After DNA damage, proliferating cells could actively slow down the DNA replication through an S checkpoint to provide time for repair. We report now that there is an activated S checkpoint response in CPT-treated mammalian cells. This response is regulated by Ataxia and Rad3-related (ATR)/CHK1 pathway. Compared with their wild-type counterparts, CPT-treated Ku80-/- cells showed stronger inhibition of DNA replication. This stronger inhibition had no relationship with DNA-dependent protein kinase (DNA-PK) activity but correlated with the higher activities of ATR and the higher activities of CHK1 in such cells. Not only caffeine, the nonspecific inhibitor of ATR, or UCN-01, the nonspecific inhibitor of CHK1, but also the specific CHK1 antisense oligonucleotide abolished the stronger inhibition of DNA replication in CPT-treated Ku80-/- cells. These results in aggregate indicated that the stronger S checkpoint in CPT-treated Ku80-/- cells is regulated through the highly activated ATR/CHK1 pathway.

Original languageEnglish (US)
Pages (from-to)2483-2487
Number of pages5
JournalCancer Research
Volume62
Issue number9
StatePublished - May 1 2002

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S Phase Cell Cycle Checkpoints
Camptothecin
Ataxia
DNA Replication
Type I DNA Topoisomerase
DNA Damage
DNA-Activated Protein Kinase
Antisense Oligonucleotides
Caffeine
S Phase

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Wang, H., Wang, X., Zhou, X. Y., Chen, D. J., Li, G. C., Iliakis, G., & Wang, Y. (2002). Ku affects the ataxia and rad 3-related/CHK1-dependent S phase checkpoint response after camptothecin treatment. Cancer Research, 62(9), 2483-2487.

Ku affects the ataxia and rad 3-related/CHK1-dependent S phase checkpoint response after camptothecin treatment. / Wang, Hongyan; Wang, Xiang; Zhou, Xiang Yang; Chen, David J.; Li, Gloria C.; Iliakis, George; Wang, Ya.

In: Cancer Research, Vol. 62, No. 9, 01.05.2002, p. 2483-2487.

Research output: Contribution to journalArticle

Wang, H, Wang, X, Zhou, XY, Chen, DJ, Li, GC, Iliakis, G & Wang, Y 2002, 'Ku affects the ataxia and rad 3-related/CHK1-dependent S phase checkpoint response after camptothecin treatment', Cancer Research, vol. 62, no. 9, pp. 2483-2487.
Wang H, Wang X, Zhou XY, Chen DJ, Li GC, Iliakis G et al. Ku affects the ataxia and rad 3-related/CHK1-dependent S phase checkpoint response after camptothecin treatment. Cancer Research. 2002 May 1;62(9):2483-2487.
Wang, Hongyan ; Wang, Xiang ; Zhou, Xiang Yang ; Chen, David J. ; Li, Gloria C. ; Iliakis, George ; Wang, Ya. / Ku affects the ataxia and rad 3-related/CHK1-dependent S phase checkpoint response after camptothecin treatment. In: Cancer Research. 2002 ; Vol. 62, No. 9. pp. 2483-2487.
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