A Protease Pathway for the Repair of Topoisomerase II-DNA Covalent Complexes

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

doi:10.1074/jbc.m604149200

Cited by 130 publications

(168 citation statements)

References 41 publications

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“…Several studies suggest that the toxicity exerted by TOP2 inhibitors is due to proteasomal processing of TOP2-DNA adducts that exposes TOP2-concealed DSB. 25,26 In agreement with this model, the proteasome inhibitor MG132 attenuated (Po0.05) DOXOinduced lethality in myotubes (Figure 6d). Conversely, the radical oxygen species (ROS)-scavenger N-acetylcysteine (NAC) did not affect the cytotoxicity induced by DOXO (Figure 6d), indicating that in muscle cells, the redox cycling ability of DOXO does not have a major role in toxicity.…”

Section: Resultssupporting

confidence: 63%

DNA damage response by single-strand breaks in terminally differentiated muscle cells and the control of muscle integrity

et al. 2012

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DNA single-strand breaks (SSB) formation coordinates the myogenic program, and defects in SSB repair in post-mitotic cells have been associated with human diseases. However, the DNA damage response by SSB in terminally differentiated cells has not been explored yet. Here we show that mouse post-mitotic muscle cells accumulate SSB after alkylation damage, but they are extraordinarily resistant to the killing effects of a variety of SSB-inducers. We demonstrate that, upon SSB induction, phosphorylation of H2AX occurs in myotubes and is largely ataxia telangiectasia mutated (ATM)-dependent. However, the DNA damage signaling cascade downstream of ATM is defective as shown by lack of p53 increase and phosphorylation at serine 18 (human serine 15). The stabilization of p53 by nutlin-3 was ineffective in activating the cell death pathway, indicating that the resistance to SSB inducers is due to defective p53 downstream signaling. The induction of specific types of damage is required to activate the cell death program in myotubes. Besides the topoisomerase inhibitor doxorubicin known for its cardiotoxicity, we show that the mitochondria-specific inhibitor menadione is able to activate p53 and to kill effectively myotubes. Cell killing is p53-dependent as demonstrated by full protection of myotubes lacking p53, but there is a restriction of p53-activated genes. This new information may have important therapeutic implications in the prevention of muscle cell toxicity. Cells respond to genotoxic stress by activating a signaling cascade known as the DNA damage response (DDR). The DDR is a complex interlaced network comprised of DNA damage repair factors and cell cycle regulators. 1 Our knowledge of the mechanisms of DDR mainly relies on studies conducted in proliferating cells, in which the cell cycle machinery is integrated with the DNA damage signaling. Much less is known in post-mitotic cells that undergo irreversible cell cycle withdrawal. DNA repair is strongly affected by the exit from the cell cycle as revealed by downregulation of the major DNA repair pathways. 2 This occurs during differentiation-associated gene reprogramming at transcriptional level as in the case of genes coding for proteins shared by DNA repair and replication (e.g., replicative DNA polymerases, Flap structure-specific endonuclease 1, proliferating cell nuclear antigen and DNA ligase 1) 3 or repair proteins that are cell-cycle related (e.g., XRCC1 (X-ray repair complementing defective repair in Chinese hamster cells 1), uracil-DNA glycosylase). 4,5 Alternatively, post-translational modifications may modify the efficiency of specific DNA repair components as in the case of transcription factor II H that, because of reduced ubiquitination, may lead to decreased global genomic nucleotide excision repair typical of differentiated cells. 6 Exposure of single-stranded (ss) DNA and/or the generation of double-strand breaks (DSB) are powerful activators of DDR by recruiting and activating two protein kinases, ataxia telangiectasia and Rad3-related (ATR)...

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Section: Resultssupporting

confidence: 63%

DNA damage response by single-strand breaks in terminally differentiated muscle cells and the control of muscle integrity

et al. 2012

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“…Cellular determinants for the activation of cellular responses to the protein-linked DNA damage have started to be revealed [12][13][14][15]. In this study, we have used the CPT-induced TOP1cc to study processing pathways involved in the DDR activation responding to TOP1-linked DNA breakage.…”

Section: Discussionmentioning

confidence: 99%

“…The UPP pathway and Tdp1 have been shown to be involved in the removal of TOP1 from enzyme-linked DNA breaks. Owing to the ability in removal of enzyme from cleavable complex, the UPP pathway and Tdp1 have thus been suggested to participate in the repair of TOP1-and/or TOP2-linked DNA breaks [6,[12][13][14][15]. In addition, the CPT-induced degradation of TOP1 (namely TOP1 downregulation) is initiated by the collision between RNA polymerase and TOP1cc, followed by proteolysis through the UPP pathway, like those observed in the process of TOP2cc downregulation [4,14,22,23].…”

Section: Introductionmentioning

confidence: 99%

“…The structural information [8][9][10] and recent studies on the roles of cellular activities and pathways for TOPcc-induced DDR [11][12][13][14][15][16] have suggested that the interactions between TOPcc and cellular activities, such as proteasomal degradation, might process DNA break embedded in the enzyme center into more detectable DNA lesions. These DNA lesions are differentially detected and then followed by the activation of various DDR.…”

Section: Introductionmentioning

confidence: 99%

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Cellular processing determinants for the activation of damage signals in response to topoisomerase I-linked DNA breakage

et al. 2010

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“…A critical step in the reaction catalyzed by topo II involves the formation of a topo II-DNA covalent complex, referred to as the cleavable complex, in which each topo II homodimeric subunit is covalently linked to the 5'-phosphoryl ends of the broken DNA strand (11,12). Under normal circumstances, the cleavable complex is a short-lived reaction intermediate.…”

Section: Introductionmentioning

confidence: 99%

Proteasomal inhibition stabilizes topoisomerase IIα protein and reverses resistance to the topoisomerase II poison ethonafide (AMP-53, 6-ethoxyazonafide)

Congdon

Pourpak

Escalante

et al. 2008

Biochemical Pharmacology

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Multiple myeloma (MM) is an incurable malignancy of plasma cells. Although multiple myeloma patients often respond to initial therapy, the majority of patients will relapse with disease that is refractory to further drug treatment. Thus, new therapeutic strategies are needed. One common mechanism of acquired drug resistance involves a reduction in the expression or function of the drug target. We hypothesized that the cytotoxic activity of topoisomerase II (topo II) poisons could be enhanced, and drug resistance overcome, by increasing the expression and activity of the drug target, topo II in myeloma cells. To test this hypothesis, we evaluated the cytotoxicity of the anthracenecontaining topo II poison, ethonafide (AMP-53/6-ethoxyazonafide), in combination with the proteasome inhibitor bortezomib (PS-341/Velcade). Combination drug activity studies were done in 8226/S myeloma cells and its drug resistant subclone, 8226/Dox1V. We found that a 24-hour treatment of cells with bortezomib maximally increased topo IIα protein expression and activity, and consistently increased the cytotoxicity of ethonafide in the 8226/S and 8226/Dox1V cell lines. This increase in cytotoxicity corresponded to an increase in DNA double-strand breaks, as measured by the neutral comet assay. Therefore, increasing topo IIα expression through inhibition of proteasomal degradation increased DNA double-strand breaks and enhanced the cytotoxicity of the topo II poison ethonafide. These data suggest that bortezomib-mediated stabilization of topo IIα expression may potentiate the cytotoxic activity of topo II poisons and thereby, provide a strategy to circumvent drug resistance.

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A Protease Pathway for the Repair of Topoisomerase II-DNA Covalent Complexes

Cited by 130 publications

References 41 publications

DNA damage response by single-strand breaks in terminally differentiated muscle cells and the control of muscle integrity

DNA damage response by single-strand breaks in terminally differentiated muscle cells and the control of muscle integrity

Cellular processing determinants for the activation of damage signals in response to topoisomerase I-linked DNA breakage

Proteasomal inhibition stabilizes topoisomerase IIα protein and reverses resistance to the topoisomerase II poison ethonafide (AMP-53, 6-ethoxyazonafide)

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