Catalytic inhibitors of DNA topoisomerase II

Andoh, Toshiwo; Ishida, Ryoji

doi:10.1016/s0167-4781(98)00133-x

Cited by 228 publications

(201 citation statements)

References 82 publications

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“…To test whether ICRF-193 preferentially inhibits TOP2␤ over TOP2␣, the effect of ICRF-193 on TOP2-DNA covalent complexes was determined by the band-depletion assay. The antagonistic effect of ICRF-193 on TOP2 poisons-induced TOP2-DNA covalent complexes has been noted before (22). As shown in Fig.…”

Section: Resultssupporting

confidence: 57%

The topoisomerase IIβ circular clamp arrests transcription and signals a 26S proteasome pathway

Xiao

Mao

Desai

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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It has been proposed that the topoisomerase II (TOP2)␤-DNA covalent complex arrests transcription and triggers 26S proteasome-mediated degradation of TOP2␤. It is unclear whether the initial trigger for proteasomal degradation is due to DNA damage or transcriptional arrest. In the current study we show that the TOP2 catalytic inhibitor 4,4-(2,3-butanediyl)-bis(2,6-piperazinedione) (ICRF-193), which traps TOP2 into a circular clamp rather than the TOP2-DNA covalent complex, can also arrest transcription. Arrest of transcription, which is TOP2␤-dependent, is accompanied by proteasomal degradation of TOP2␤. Different from TOP2 poisons and other DNA-damaging agents, ICRF-193 did not induce proteasomal degradation of the large subunit of RNA polymerase II. These results suggest that proteasomal degradation of TOP2␤ induced by the TOP2-DNA covalent complex or the TOP2 circular clamp is due to transcriptional arrest but not DNA damage. By contrast, degradation of the large subunit of RNA polymerase II is due to a DNA-damage signal.

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Section: Resultssupporting

confidence: 57%

The topoisomerase IIβ circular clamp arrests transcription and signals a 26S proteasome pathway

Xiao

Mao

Desai

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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“…The difference in clastogenicity between merbarone and ICRF-193 may depend on their respective molecular modes of action to topo II. Merbarone primarily blocks 16 topo II-mediated DNA strand breaks, thus forming pre-cleavable complexes, while ICRF-193 is believed to stabilize the closed clamp form of topo II by creating post-passage complexes [7]. Supposing that DNA torsional stress can be relieved by post-passage complexes, the generation of DNA strand breaks may be circumvented even in the presence of ICRF-193.…”

Section: Discussionmentioning

confidence: 99%

“…Etoposide belongs to a class of topo II poisons that stabilize enzyme-DNA cleavable complexes [5]. and merbarone belong to another class of topo II inhibitors, referred to as catalytic inhibitors [6,7].…”

Section: Introductionmentioning

confidence: 99%

“…The medium used for culturing oocytes and androgenones under 5 % CO2 in air was CZB [25] temporarily kept in CZB medium at 37 °C and then transferred into a droplet (10 µl) of Hepes-CZB medium containing 5 µg/ml cytochalasin B (Sigma-Aldrich) and enucleated as described elsewhere [26]. The enucleation 7 was performed at room temperature. The enucleated oocytes were thoroughly washed with CZB medium and kept in the medium at 37 °C until use.…”

Section: Introductionmentioning

confidence: 99%

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Chromosome analysis of mouse one-cell androgenones derived from a sperm nucleus exposed to topoisomerase II inhibitors at pre- and post-fertilization stages

Tateno

Kamiguchi

2004

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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“…Among these, bis-2,6-dioxopiperazines, such as meso-2,3-bis(2,6-dioxopiperazin-4-yl)butane (ICRF-193), have been most extensively analyzed thus far. Earlier biochemical studies have suggested that ICRF-193 inhibits topo II by trapping the enzyme in the form of a closed protein clamp (topo II clamp) (32,33). However, more recent studies suggest that ICRF-193 is not a pure catalytic inhibitor; rather, it may act as a topo II poison (34 -38).…”

mentioning

confidence: 99%

Hypersensitivity of Nonhomologous DNA End-joining Mutants to VP-16 and ICRF-193

Adachi

Suzuki

Iiizumi

et al. 2003

Journal of Biological Chemistry

139

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A number of clinically useful anticancer drugs, including etoposide (VP-16), target DNA topoisomerase (topo) II. These drugs, referred to as topo II poisons, stabilize cleavable complexes, thereby generating DNA doublestrand breaks. Bis-2,6-dioxopiperazines such as ICRF-193 also inhibit topo II by inducing a distinct type of DNA damage, termed topo II clamps, which has been believed to be devoid of double-strand breaks. Despite the biological and clinical importance, the molecular mechanisms for the repair of topo II-mediated DNA damage remain largely unknown. Here, we perform genetic analyses using the chicken DT40 cell line to investigate how DNA lesions caused by topo II inhibitors are repaired. Notably, we show that LIG4 ؊/؊ and KU70 ؊/؊ cells, which are defective in nonhomologous DNA endjoining (NHEJ), are extremely sensitive to both VP-16 and ICRF-193. In contrast, RAD54 ؊/؊ cells (defective in homologous recombination) are much less hypersensitive to VP-16 than the NHEJ mutants and, more importantly, are not hypersensitive to ICRF-193. Our results provide the first evidence that NHEJ is the predominant pathway for the repair of topo II-mediated DNA damage; that is, cleavable complexes and topo II clamps. The outstandingly increased cytotoxicity of topo II inhibitors in the absence of NHEJ suggests that simultaneous inhibition of topo II and NHEJ would provide a powerful protocol in cancer chemotherapy involving topo II inhibitors.DNA double-strand breaks (DSBs) 1 can be caused by a variety of exogenous and endogenous agents, posing a major threat to genome integrity. If left unrepaired, DSBs may cause cell death (1, 2). Vertebrate cells have evolved two major pathways for repairing DSBs, homologous recombination (HR) and nonhomologous DNA end-joining (NHEJ) (2)(3)(4)(5).With the use of homologous DNA sequences, HR allows for accurate repair of DSBs. In eukaryotic cells, the HR reaction is performed by a wide variety of proteins including Rad51, Rad52, and Rad54 (2). In vitro, Rad51 protein assembles with single-stranded DNA to form the helical nucleoprotein filament that promotes DNA strand exchange, a basic step of HR (6 -8). Rad54 protein is shown to interact with and stabilize the Rad51 nucleoprotein filament, stimulating its DNA pairing activity (9, 10). Interestingly, although Rad52 protein plays a pivotal role in DSB repair in Saccharomyces cerevisiae, the role of vertebrate and Schizosaccharomyces pombe Rad52 is much less significant (11)(12)(13).In contrast to accurate repair by HR, NHEJ can lead to imprecise joining of DSB ends. It has been well established that NHEJ is responsible for V(D)J recombination in lymphocytes (3, 5). The NHEJ reaction relies on Ku (a heterodimer of Ku70 and Ku86), DNA-PKcs, Artemis, Xrcc4, and DNA ligase IV (the LIG4 gene product) (3,5,14). Extensive biochemical studies propose a model for the mechanism of NHEJ (3,5,14,15). First, Ku binds to the ends of a DSB and recruits the DNAPKcs⅐Artemis complex. This complex would then trim the ends to make the ends ligatable. A...

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Catalytic inhibitors of DNA topoisomerase II

Cited by 228 publications

References 82 publications

The topoisomerase IIβ circular clamp arrests transcription and signals a 26S proteasome pathway

The topoisomerase IIβ circular clamp arrests transcription and signals a 26S proteasome pathway

Chromosome analysis of mouse one-cell androgenones derived from a sperm nucleus exposed to topoisomerase II inhibitors at pre- and post-fertilization stages

Hypersensitivity of Nonhomologous DNA End-joining Mutants to VP-16 and ICRF-193

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