Safeguarding genetic information in Drosophila

Su, Tin Tin

doi:10.1007/s00412-011-0342-9

Cited by 6 publications

(4 citation statements)

References 74 publications

(82 reference statements)

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“…As such, it has been used to the study the genetic mechanisms of cancer for nearly 40 years (Gateff and Schneiderman 1974; Gateff 1978), and multiple facets of carcinogenesis have been investigated in that time (reviewed in Rudrapatna et al 2012). Drosophila also has proven to be an invaluable tool to research the effects of chemotherapeutic drugs (Boyd and Setlow 1976; Radcliffe et al 2002; Jaklevic et al 2006; Edwards et al 2011; Gladstone and Su 2011) and the effects of mutations in key DNA repair genes (reviewed in Su 2011). …”

mentioning

confidence: 99%

Common Variants ofDrosophila melanogasterCyp6d2 Cause Camptothecin Sensitivity and Synergize With Loss of Brca2

Thomas

Hui

South

et al. 2013

G3 Genes|Genomes|Genetics

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Many chemotherapeutic agents selectively target rapidly dividing cells, including cancer cells, by causing DNA damage that leads to genome instability and cell death. We used Drosophila melanogaster to study how mutations in key DNA repair genes affect an organism’s response to chemotherapeutic drugs. In this study, we focused on camptothecin and its derivatives, topotecan and irinotecan, which are type I topoisomerase inhibitors that create DNA double-strand breaks in rapidly dividing cells. Here, we describe two polymorphisms in Drosophila Cyp6d2 that result in extreme sensitivity to camptothecin but not topotecan or irinotecan. We confirmed that the sensitivity was due to mutations in Cyp6d2 by rescuing the defect with a wild-type copy of Cyp6d2. In addition, we showed that combining a cyp6d2 mutation with mutations in Drosophila brca2 results in extreme sensitivity to camptothecin. Given the frequency of the Cyp6d2 polymorphisms in publcly available Drosophila stocks, our study demonstrates the need for caution when interpreting results from drug sensitivity screens in Drosophila and other model organisms. Furthermore, our findings illustrate how genetic background effects can be important when determining the efficacy of chemotherapeutic agents in various DNA repair mutants.

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confidence: 99%

Common Variants ofDrosophila melanogasterCyp6d2 Cause Camptothecin Sensitivity and Synergize With Loss of Brca2

Thomas

Hui

South

et al. 2013

G3 Genes|Genomes|Genetics

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“…Drosophila and vertebrate Chk1 are involved in SAC activation (16,48,49). The S. pombe crb2 mutant arrests in prometaphase in a Chk1-dependent fashion in response to replication stress induced by a topoisomerase I inhibitor (11).…”

Section: Discussionmentioning

confidence: 99%

“…When the DNA damage checkpoint is activated, Chk1 phosphorylates Cdc25 and Wee1, which maintain Cdc2 in an inactive state, resulting in cell cycle arrest at the G 2 /M transition (7)(8)(9)(10). A link between DNA damage and the SAC in many organisms, including Saccharomyces cerevisiae, Schizosaccharomyces pombe, Drosophila, and humans (11)(12)(13)(14)(15)(16)(17)(18), has been suggested. However, the molecular details of this link are not well understood.…”

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confidence: 99%

Rad51-Dependent Aberrant Chromosome Structures at Telomeres and Ribosomal DNA Activate the Spindle Assembly Checkpoint

et al. 2014

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bThe spindle assembly checkpoint (SAC) monitors defects in kinetochore-microtubule attachment or lack of tension at kinetochores and arrests cells at prometaphase. In fission yeast, the double mutant between pot1⌬ and the helicase-dead point mutant of the RecQ helicase Rqh1 gene (rqh1-hd) accumulates Rad51-dependent recombination intermediates at telomeres and enters mitosis with those intermediates. Here, we found that SAC-dependent prometaphase arrest occurred more frequently in pot1⌬ rqh1-hd double mutants than in rqh1-hd single mutants. SAC-dependent prometaphase arrest also occurred more frequently in rqh1-hd single mutants after cells were released from DNA replication block compared to the rqh1-hd single mutant in the absence of exogenous insult to the DNA. In both cases, Mad2 foci persisted longer than usual at kinetochores, suggesting a defect in kinetochore-microtubule attachment. In pot1⌬ rqh1-hd double mutants and rqh1-hd single mutants released from DNA replication block, SAC-dependent prometaphase arrest was suppressed by the removal of the recombination or replication intermediates. Our results indicate that the accumulation of recombination or replication intermediates induces SAC-dependent prometaphase arrest, possibly by affecting kinetochore-microtubule attachment.

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“…Camptothecin is a competitive inhibitor of this enzyme. Camptothecin, the crystalized ligand of cyp2d6 and its derivatives stabilize the normally transient covalent link between DNA and Top1, thereby interfering with the relaxation of supercoiling that occurs during events requiring DNA unwinding, such as replication or transcription [27,28,29]. Previous finding proposes that the accumulation of regressed forks or supercoiled DNA is responsible for the toxic effects of camptothecin [30].…”

Section: Tramadol Detoxification Potential Of Cyp2d6mentioning

confidence: 99%

Computational study on the molecular interactions of tramadol with selected antioxidant and detoxification enzymes in Drosophila melanogaster

Adeniran¹

2021

GSC Biol. and Pharm. Sci.

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Tramadol is a potent analgesic medication prescribed worldwide for treatment of acute and chronic pains. Its relative tendency to be abused has become a public health concern. This study was designed to evaluate the molecular interactions of tramadol with selected antioxidant and detoxification enzymes of Drosophila melanogaster. The structures of CYP2D6, catalase and defense repressor 1 were retrieved from protein database (PubMed, Swiss model) while tramadol 2D structure was obtained from PubChem repository and prepared using LigPrep scripts as implemented in Small-Molecule Drug Discovery Suite of Schrödinger. 2D structure of tramadol was docked into the protein model binding site using Glide software from Schrodinger. The result revealed that, on the binding pocket of CYP2D6, tramadol and CYP2D6 inhibitor bind the protein pocket via hydrogen bond. The hydroxyl group of tramadol and the inhibitor interacts with the C=O groups of the residues Glu 128 and Lys 264 on the protein pocket respectively. Tramadol binds with higher affinity with a docking score of -4.581 kcal/mol when compared with the inhibitor which gave a docking score of -1.865 kcal/mol. With catalase, tramadol and the crystalized ligands were observed to exhibit hydrogen bonding with Ala 64 residue on the protein binding pocket with docking score of -2.348 kcal/mol and -3.431 kcal/mol respectively. The ability of tramadol to interact with these enzymes, strongly suggests that tramadol treatment may induce oxidative stress and at high dose might result in cellular toxicity. Therefore, the toxic effects of tramadol should be of concern despite the important role it plays in pain management.

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Safeguarding genetic information in Drosophila

Cited by 6 publications

References 74 publications

Common Variants ofDrosophila melanogasterCyp6d2 Cause Camptothecin Sensitivity and Synergize With Loss of Brca2

Common Variants ofDrosophila melanogasterCyp6d2 Cause Camptothecin Sensitivity and Synergize With Loss of Brca2

Rad51-Dependent Aberrant Chromosome Structures at Telomeres and Ribosomal DNA Activate the Spindle Assembly Checkpoint

Computational study on the molecular interactions of tramadol with selected antioxidant and detoxification enzymes in Drosophila melanogaster

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