A protease pathway for the repair of topoisomerase II-DNA covalent complexes

Ailing Zhang, Yi Lisa Lyu, Chao Po Lin, Nai Zhou, Anna M. Azarova, Laurence M. Wood, Leroy F. Liu

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115 Citations (Scopus)


Despite rapid advances in the field of DNA repair, little is known about the repair of protein-DNA adducts. Previous studies have demonstrated that topoisomerase II (TopII)-DNA adducts (TopII-DNA covalent complexes) are rapidly degraded by the proteasome. It has been hypothesized that proteasomal degradation of TopII-DNA covalent adducts exposes TopII-concealed DNA double-strand breaks (DSBs) for repair. To test this hypothesis, the anticancer drug, VP-16 (etoposide), was employed to induce TopII-DNA covalent complexes in mammalian cells, and the involvement of proteasome in processing TopII-DNA covalent complexes into DSBs was investigated. Consistent with the hypothesis, VP-16-induced DSBs as monitored by neutral comet assay, as well as DNA damage signals (e.g. γ-H2AX) were significantly reduced in the presence of the proteasome inhibitor, MG132. Using both top2β knock-out mouse embryonic fibroblasts and Top2β small interfering RNA knockdown PC12 cells, as well as postmitotic neurons in which TopIIβ was absent, we showed that VP-16-induced DNA damage signals were attenuated upon proteasome inhibition, suggesting the involvement of proteasome in the repair/processing of both TopIIα-DNA and TopIIβ-DNA adducts. By contrast, hydrogen peroxide-induced γ-H2AX was unaffected upon proteasome inhibition, suggesting a specific requirement of the proteasome pathway in the processing of TopII-DNA covalent complexes into DNA damage.

Original languageEnglish
Pages (from-to)35997-36003
Number of pages7
JournalJournal of Biological Chemistry
Issue number47
Publication statusPublished - Nov 24 2006
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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