Ataxia telangiectasia mutated activation by transcription‐ and topoisomerase I‐induced DNA double‐strand breaks

Sordet, Olivier; Redon, Christophe E.; Guirouilh‐Barbat, Josée; Smith, Susan; Solier, Stéphanie; Douarre, Céline; Conti, Chiara; Nakamura, Asako; Das, Benu Brata; Nicolas, Estelle; Kohn, Kurt W.; Bonner, William M.; Pommier, ﻿Yves

doi:10.1038/embor.2009.97

Cited by 215 publications

(255 citation statements)

References 29 publications

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“…Excessive ROS, e.g., that generated by IR, induces mitochondrial apoptosis, because mitochondrial DNA is highly sensitive to mutations caused by endogenous ROS (47,48). DSB by ROS can arise when ROS-induced DNA damage interferes with either DNA replication or transcription (49,50). In the present study, intracellular ROS levels in HT1080 cells were increased by SE I treatment, and the cytotoxic effects enhanced by co-treatment with ZOL were reduced by NAC treatment.…”

Section: Discussionsupporting

confidence: 53%

“…The individual IC 50 values for ZOL and radiation after 72 h of exposure were 1.77 µM and 4.08 Gy, respectively (Fig. 1A).…”

Section: Co-treatment With Zol and Ir Shows Enhanced Inhibitory Effecmentioning

confidence: 99%

“…1A). Based on the IC 50 values, we investigated the combined effects of ZOL at concentrations lower than the IC 50 with radiation at a lower dose than the IC 50 .…”

Section: Co-treatment With Zol and Ir Shows Enhanced Inhibitory Effecmentioning

confidence: 99%

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Zoledronic acid significantly enhances radiation-induced apoptosis against human fibrosarcoma cells by inhibiting radioadaptive signaling

Koto

Murata

Kimura

et al. 2012

International Journal of Oncology

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Abstract. Zoledronic acid (ZOL), a third-generation bisphosphonate, inhibits bone resorption, as well as exhibiting direct antitumor activity. To date, however, the combined effects of ZOL and ionizing radiation (IR) have not been assessed in patients with soft tissue sarcoma. We have, therefore, assessed the combined effects of ZOL and IR in fibrosarcoma cells. HT1080 fibrosarcoma cells were treated with ZOL and/or IR, together or sequentially and the antitumor effects were assessed. We found that ZOL significantly enhanced IR-induced apoptosis, especially when cells were treated with ZOL followed by IR. We, therefore, assessed the detailed mechanism of sequential treatment with ZOL and IR. Cells in G2 and M phases, the most radiosensitive phases of the cell cycle, were not increased by low concentrations of ZOL. However, the levels of expression of Akt, ERK1/2 and NF-κB proteins, all of which are related to radioadaptive resistance, were increased within a short time after irradiation with 3 Gy, and this expression was inhibited by a low concentration of ZOL, which blocked the prenylation of small GTPases. This sequential treatment also increased the generation of reactive oxygen species (ROS). These results suggest that the combination of ZOL with IR may be beneficial in treating patients with soft tissue sarcoma.

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Section: Discussionsupporting

confidence: 53%

“…The individual IC 50 values for ZOL and radiation after 72 h of exposure were 1.77 µM and 4.08 Gy, respectively (Fig. 1A).…”

Section: Co-treatment With Zol and Ir Shows Enhanced Inhibitory Effecmentioning

confidence: 99%

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Zoledronic acid significantly enhances radiation-induced apoptosis against human fibrosarcoma cells by inhibiting radioadaptive signaling

Koto

Murata

Kimura

et al. 2012

International Journal of Oncology

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“…16 Recently, CPT has been shown to induce ATM activation and phosphorylation of the histone H2AX in post-mitotic neurons and lymphocytes. 12 A mechanism for DDR activation by CPT has been proposed where TOP1cc would produce transcription arrests with R-loop formation and generation of DSBs that would in turn activate ATM and trigger phosphorylation of H2AX. 32 Whether this occurs by the same mechanism in muscle cells has not been explored, but the lack of p53 activation indicates that the signaling cascade differs from that triggered by TOP2-mediated DSB (as after DOXO treatment).…”

Section: Discussionmentioning

confidence: 99%

“…ATM is also activated in post-mitotic cells (human lymphocytes and rat cortical neurons) by camptothecin (CPT) that selectively traps Topoisomerase (TOP)1-linked SSB (TOP1 cleavage complexes, TOP1cc). 12 Phosphorylation of ATM by cyclin-dependent kinase 5 seems to mediate DNA damage signaling and regulate neuronal death upon CPT treatment, 13 but whether this is limited to neural tissue remains to be addressed. The complexity of DDR activation in post-mitotic cells emerges also from studies conducted in differentiated muscle cells where activation of DDR was described upon induction of DSB, but a blockade of signaling was reported downstream of ATM upon exposure to ionizing radiation (IR) but not to the TOP2 inhibitor doxorubicin (DOXO).…”

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confidence: 99%

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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DNA Topoisomerase Targeting Drugs

Thomas

Bates

Figg

et al. 2017

Holland‐Frei Cancer Medicine

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Overview DNA topoisomerase targeting drugs are widely used in the treatment of multiple cancers. These drugs act by generating topoisomerase‐linked DNA breaks and by blocking the religation of the cleavage complexes. Although topoisomerase targeting drugs have a wide spectrum of activity, structural, pharmacokinetic, and pharmacodynamic characteristics somewhat limit their efficacy and safety. To circumvent these limitations and to further exploit its activity, newer inhibitors‐ including novel formulations and those that achieve targeted delivery‐ are being developed. Recently described mechanisms that underlie cellular sensitivity to these agents will enable us to predict the activity of topoisomerase targeting drugs and to precisely select patients who are most likely to benefit. Understanding the genetic variants in drug metabolizing enzymes, transporters, and other proteins that influence the pharmacology of these drugs will allow for further individualizing the use of these drugs.

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Ataxia telangiectasia mutated activation by transcription‐ and topoisomerase I‐induced DNA double‐strand breaks

Cited by 215 publications

References 29 publications

Zoledronic acid significantly enhances radiation-induced apoptosis against human fibrosarcoma cells by inhibiting radioadaptive signaling

Zoledronic acid significantly enhances radiation-induced apoptosis against human fibrosarcoma cells by inhibiting radioadaptive signaling

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

DNA Topoisomerase Targeting Drugs

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