Topoisomerase II Poisoning by ICRF-193

Huang, Kuan Chun; Gao, Hanlin; Yamasaki, Edith; Grabowski, Dale; Liu, Shujun; Shen, Linus L.; Chan, Kenneth K.; Ganapathi, Ram; Snapka, Robert M.

doi:10.1074/jbc.m104383200

Cited by 79 publications

(72 citation statements)

References 30 publications

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“…However, a more recent study has suggested that ICRF-193 can trap a substantial amount of covalent TOP2␤ (but not TOP2␣)-DNA complexes if Gdn⅐HCl rather than SDS is used to terminate the reaction (28). Their results could explain why ICRF-193 induces preferential degradation of TOP2␤, because only TOP2␤ can be trapped efficiently by ICRF-193 into covalent TOP2␤-DNA complexes.…”

Section: Icrf-193 Does Not Trap Top2-dna Covalent Complexesmentioning

confidence: 95%

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: Icrf-193 Does Not Trap Top2-dna Covalent Complexesmentioning

confidence: 95%

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 is also possible that the isoform selectivity of ICRF-193 may contribute to the difference in the involvement of HR. ICRF-193 has recently been shown to target topo II␤ to a greater extent than it targets topo II␣ (46,52). Possibly, the recovery from topo II␤ inhibition may have a stronger preference for NHEJ than topo II␣ inhibition.…”

Section: Discussionmentioning

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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“…First, it specifically inactivates only the ␣ isoform and is certain to remove any structural role. Second, it avoids the complication of side effects, especially DNA DSBs, which were initially thought to be limited to topoII "poisons" such as etoposide, but more recently linked to catalytic inhibitors such as ICRF-193 (van Hille et al, 1999;Huang et al, 2001;Kobayashi et al, 2001;Wang and Eastmond, 2002;. Third, conditional mutagenesis allows complementation studies to be done.…”

Section: Introductionmentioning

confidence: 99%

Construction, Characterization, and Complementation of a Conditional-Lethal DNA Topoisomerase IIα Mutant Human Cell Line

Carpenter

Porter

2004

MBoC

136

175

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DNA Topoisomerase II␣ (topoII␣) is a DNA decatenating enzyme, abundant constituent of mammalian mitotic chromosomes, and target of numerous antitumor drugs, but its exact role in chromosome structure and dynamics is unclear. In a powerful new approach to this important problem, with significant advantages over the use of topoII inhibitors or RNA interference, we have generated and characterized a human cell line (HTETOP) in which >99.5% topoII␣ expression can be silenced in all cells by the addition of tetracycline. TopoII␣-depleted HTETOP cells enter mitosis and undergo chromosome condensation, albeit with delayed kinetics, but normal anaphases and cytokineses are completely prevented, and all cells die, some becoming polyploid in the process. Cells can be rescued by expression of topoII␣ fused to green fluorescent protein (GFP), even when certain phosphorylation sites have been mutated, but not when the catalytic residue Y805 is mutated. Thus, in addition to validating GFP-tagged topoII␣ as an indicator for endogenous topoII␣ dynamics, our analyses provide new evidence that topoII␣ plays a largely redundant role in chromosome condensation, but an essential catalytic role in chromosome segregation that cannot be complemented by topoII␤ and does not require phosphorylation at serine residues 1106, 1247, 1354, or 1393. INTRODUCTIONType II topoisomerases are ubiquitous, highly conserved proteins that catalyze the passage of one DNA duplex through another, creating a transient double-strand break (DSB) in the latter (Watt and Hickson, 1994;Wang, 2002). Studies in a variety of systems indicate that topoII is essential for cellular viability and that it plays a key role in chromosome segregation. Thus, the abnormal cell divisions seen in yeast top2 mutants (Holm et al., 1985;Uemura and Yanagida, 1986), and in vertebrate cells treated with topoII inhibitors (Downes et al., 1991;Ishida et al., 1991Ishida et al., , 1994Haraguchi et al., 2000) are consistent with the unique ability of topoII to resolve the sister chromatids catenations generated when DNA replication forks meet (Wang, 2002). TopoII has been implicated in mammalian centromere function (Floridia et al., 2000;Spence et al., 2002), and it has been suggested that topoII in yeast may play a role in centromeric chromatin structure (Bachant et al., 2002). Further work is required to understand the relationship between any such structural role, topoII-mediated chromatid decatenation, and the role of the cohesin complex (Nasmyth, 2002) in maintaining sister chromatid cohesion until anaphase (Bernard and Allshire, 2002).TopoII also has been implicated in DNA recombination, replication, transcription, and chromosome condensation (Watt and Hickson, 1994;Wang, 2002). Of these, chromosome condensation is the only process in which topoII is widely reported to play an essential role (Koshland and Strunnikov, 1996;Losada and Hirano, 2001;Swedlow and Hirano, 2003), but the data are equivocal. Genetic analyses suggest that topoII is required for chromosome condensation in Sc...

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Topoisomerase II Poisoning by ICRF-193

Cited by 79 publications

References 30 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

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

Construction, Characterization, and Complementation of a Conditional-Lethal DNA Topoisomerase IIα Mutant Human Cell Line

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