β-lapachone Activates a Mre11p-Tel1p G1/S Checkpoint in Budding Yeast

Menacho‐Marquez, Mauricio; Murguía, José Ramón

doi:10.4161/cc.5.21.3394

Cited by 12 publications

(16 citation statements)

References 39 publications

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“…22 This finding was later confirmed in human cells, 23 thus validating our experimental approach. To gain further insights into the molecular mechanism of b-lap action, we analyzed the gene expression profile of yeast cells treated with b-lap using cDNA microarrays.…”

Section: Analysis Of B-lap Transcriptomal Program Triggered In Yeastsupporting

confidence: 68%

“…Initially it was reported that b-lap cytotoxicity did not involve DNA damage, but recently we and others groups have demonstrated that b-lapinduced cell death is initiated by the induction of DNA damage and checkpoint activation. 22,26 To further characterize the molecular mechanism of b-lap-induced cell death, we analyzed the profile of gene expression of WT yeast cells treated with the drug. As expected, categories as ROS response and electron transport were present in this analysis (Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…We have previously reported that b-lap activates in yeast a G1/S checkpoint in a Mec1p/Tel1p and XMR complex related fashion, what could be of significance for b-lap anti-tumor activity, given the conserved nature of this checkpoint. 22 Here we present a challenge for the reported mechanism of action of b-lap. Inhibition of ROS production induced by b-lap in yeast did not relieve the G1/S checkpoint activation.…”

Section: Introductionmentioning

confidence: 99%

“…We reported previously that in budding yeast b-lap treatment triggered a G1/S checkpoint and increased histone H2A phosphorylation. 22 We explored whether ROS generation was involved in these responses, preincubating cells with dicoumarol before b-lap exposure. Preincubation with dicoumarol partially relieved but did not eliminate the checkpoint responses triggered by b-lap exposure (Fig.…”

Section: B-lap Cytotoxicity Is Not Mediated By Ros Production In Yeastmentioning

confidence: 99%

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eIF2 kinases mediate β-lapachone toxicity in yeast and human cancer cells

et al. 2015

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b-lapachone (b-lap) is a novel anticancer agent that selectively induces cell death in human cancer cells, by activation of the NQO1 NAD(P)H dehydrogenase and radical oxygen species (ROS) generation. We characterized the gene expression profile of budding yeast cells treated with b-lap using cDNA microarrays. Genes involved in tolerance to oxidative stress were differentially expressed in b-lap treated cells. b-lap treatment generated reactive oxygen species (ROS), which were efficiently blocked by dicoumarol, an inhibitor of NADH dehydrogenases. A yeast mutant in the mitocondrial NADH dehydrogenase Nde2p was found to be resistant to b-lap treatment, despite inducing ROS production in a WT manner. Most interestingly, DNA damage responses triggered by b-lap were abolished in the nde2D mutant. Amino acid biosynthesis genes were also induced in b-lap treated cells, suggesting that b-lap exposure somehow triggered the General Control of Nutrients (GCN) pathway. Accordingly, b-lap treatment increased phosphorylation of eIF2a subunit in a manner dependent on the Gcn2p kinase. eIF2a phosphorylation required Gcn1p, Gcn20p and Nde2p. Gcn2p was also required for cell survival upon exposure to b-lap and to elicit checkpoint responses. Remarkably, b-lap treatment increased phosphorylation of eIF2a in breast tumor cells, in a manner dependent on the Nde2p ortholog AIF, and the eIF2 kinase PERK. These findings uncover a new target pathway of b-lap in yeast and human cells and highlight a previously unknown functional connection between Nde2p, Gcn2p and DNA damage responses.

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Section: Analysis Of B-lap Transcriptomal Program Triggered In Yeastsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: B-lap Cytotoxicity Is Not Mediated By Ros Production In Yeastmentioning

confidence: 99%

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eIF2 kinases mediate β-lapachone toxicity in yeast and human cancer cells

et al. 2015

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“…Previously, we showed that exposure of NQO1-expressing cancer cells to h-lap caused ROS and DNA damage, measured by alkaline comet assays and g-H2AX formation (18). Furthermore, activation of the MRN complex following h-lap exposure was recently reported in Saccharomyces cerevisiae (27). We wanted to determine if, and which, DSB repair pathways were activated in response to h-lap by examining MRN complex recruitment.…”

Section: Resultsmentioning

confidence: 99%

Nonhomologous End Joining Is Essential for Cellular Resistance to the Novel Antitumor Agent, β-Lapachone

Bentle¹,

Reinicke

Dong

et al. 2007

Cancer Research

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Commonly used antitumor agents, such as DNA topoisomerase I/II poisons, kill cancer cells by creating nonrepairable DNA double-strand breaks (DSBs). To repair DSBs, error-free homologous recombination (HR), and/or error-prone nonhomologous end joining (NHEJ) are activated. These processes involve the phosphatidylinositol 3 ¶-kinase-related kinase family of serine/threonine enzymes: ataxia telangiectasia mutated (ATM), ATM-and Rad3-related for HR, and DNAdependent protein kinase catalytic subunit (DNA-PKcs) for NHEJ. Alterations in these repair processes can cause drug/ radiation resistance and increased genomic instability. BLapachone (B-lap; also known as ARQ 501), currently in phase II clinical trials for the treatment of pancreatic cancer, causes a novel caspase-and p53-independent cell death in cancer cells overexpressing NAD(P)H:quinone oxidoreductase-1 (NQO1). NQO1 catalyzes a futile oxidoreduction of B-lap leading to reactive oxygen species generation, DNA breaks, ;-H2AX foci formation, and hyperactivation of poly(ADP-ribose) polymerase-1, which is required for cell death. Here, we report that B-lap exposure results in NQO1-dependent activation of the MRE11-Rad50-Nbs-1 complex. In addition, ATM serine 1981, DNA-PKcs threonine 2609, and Chk1 serine 345 phosphorylation were noted; indicative of simultaneous HR and NHEJ activation. However, inhibition of NHEJ, but not HR, by genetic or chemical means potentiated B-lap lethality. These studies give insight into the mechanism by which B-lap radiosensitizes cancer cells and suggest that NHEJ is a potent target for enhancing the therapeutic efficacy of B-lap alone or in combination with other agents in cancer cells that express elevated NQO1 levels. [Cancer Res 2007;67(14):6936-45]

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Current awareness on yeast

2007

Yeast

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In order to keep subscribers up‐to‐date with the latest developments in their field, this current awareness service is provided by John Wiley & Sons and contains newly‐published material on yeasts. Each bibliography is divided into 10 sections. 1 Reviews; 2 General; 3 Biochemistry; 4 Biotechnology; 5 Cell Biology; 6 Gene Expression; 7 Genetics; 8 Physiology; 9 Medical Mycology; 10 Recombinant DNA Technology. Within each section, articles are listed in alphabetical order with respect to author. If, in the preceding period, no publications are located relevant to any one of these headings, that section will be omitted. (4 weeks journals ‐ search completed 2nd. May 2007)

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β-lapachone Activates a Mre11p-Tel1p G1/S Checkpoint in Budding Yeast

Cited by 12 publications

References 39 publications

eIF2 kinases mediate β-lapachone toxicity in yeast and human cancer cells

eIF2 kinases mediate β-lapachone toxicity in yeast and human cancer cells

Nonhomologous End Joining Is Essential for Cellular Resistance to the Novel Antitumor Agent, β-Lapachone

Current awareness on yeast

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