Sensitivity to camptothecin in Aspergillus nidulans identifies a novel gene, scaA+, related to the cellular DNA damage response

G. C M Bruschi, C. C. De Souza, M. R V Z K Fagundes, M. A C Dani, M. H S Goldman, N. R. Morris, Leroy-Fong Liu, G. H. Goldman

研究成果: 雜誌貢獻文章

16 引文 (Scopus)

摘要

The anti-cancer drug camptothecin targets eukaryotic DNA topoisomerase I by trapping the covalent complex formed between the catalytically active enzyme and DNA. We are interested in identifying factors, other than topoisomerase I, that are involved in mediating cellular sensitivity to camptothecin. To this end, we have isolated eighteen mutants that are sensitive to camptothecin (sca) in the filamentous fungus Aspergillus nidulans and characterised one of them, sca299. The mutant sca299 is hypersensitive to camptothecin, and sensitive to several different mutagenic agents and to actinomycin D. Using temperature-sensitive mutations in genes that are known to regulate the cell cycle, we showed that the camptothecin sensitivity of the mutant sca299 is not affected by a mitotic block. The abnormal nuclear morphology observed in the sca299 mutant strain suggests that the germlings might be undergoing mitosis in the presence of unrepaired DNA damage, which would result in mitotic catastrophe. The hypersensitivity of the sca299 mutant to camptothecin does not result from elevated levels of topoisomerase I mRNA or from alterations in enzyme activity. Using DNA-mediated complementation of the sca299 mutant phenotype, the scaA+ gene was cloned. This gene encodes a 594-amino acid product; moderate structural similarity suggests that the scaA gene product may be related to the human nibrin gene which encodes a product involved in DNA double-strand break repair. Strains disrupted in the scaA gene were sensitive to the anti-topoisomerase I agent berberine, the DNA cross-linking agents mitomycin C and cis-platinum, and also to t-butyl hydroperoxide, which is an inducer of oxidative stress.

原文英語
頁(從 - 到)264-275
頁數12
期刊Molecular and General Genetics
265
發行號2
出版狀態已發佈 - 2001
對外發佈Yes

指紋

Aspergillus nidulans
Camptothecin
DNA Damage
Type I DNA Topoisomerase
Genes
DNA
Berberine
tert-Butylhydroperoxide
Double-Stranded DNA Breaks
Dactinomycin
Mitomycin
Enzymes
Mitosis
Cisplatin
Cell Cycle
Hypersensitivity
Oxidative Stress
Fungi
Phenotype
Amino Acids

ASJC Scopus subject areas

  • Genetics

引用此文

Bruschi, G. C. M., De Souza, C. C., Fagundes, M. R. V. Z. K., Dani, M. A. C., Goldman, M. H. S., Morris, N. R., ... Goldman, G. H. (2001). Sensitivity to camptothecin in Aspergillus nidulans identifies a novel gene, scaA+, related to the cellular DNA damage response. Molecular and General Genetics, 265(2), 264-275.

Sensitivity to camptothecin in Aspergillus nidulans identifies a novel gene, scaA+, related to the cellular DNA damage response. / Bruschi, G. C M; De Souza, C. C.; Fagundes, M. R V Z K; Dani, M. A C; Goldman, M. H S; Morris, N. R.; Liu, Leroy-Fong; Goldman, G. H.

於: Molecular and General Genetics, 卷 265, 編號 2, 2001, p. 264-275.

研究成果: 雜誌貢獻文章

Bruschi, GCM, De Souza, CC, Fagundes, MRVZK, Dani, MAC, Goldman, MHS, Morris, NR, Liu, L-F & Goldman, GH 2001, 'Sensitivity to camptothecin in Aspergillus nidulans identifies a novel gene, scaA+, related to the cellular DNA damage response', Molecular and General Genetics, 卷 265, 編號 2, 頁 264-275.
Bruschi, G. C M ; De Souza, C. C. ; Fagundes, M. R V Z K ; Dani, M. A C ; Goldman, M. H S ; Morris, N. R. ; Liu, Leroy-Fong ; Goldman, G. H. / Sensitivity to camptothecin in Aspergillus nidulans identifies a novel gene, scaA+, related to the cellular DNA damage response. 於: Molecular and General Genetics. 2001 ; 卷 265, 編號 2. 頁 264-275.
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abstract = "The anti-cancer drug camptothecin targets eukaryotic DNA topoisomerase I by trapping the covalent complex formed between the catalytically active enzyme and DNA. We are interested in identifying factors, other than topoisomerase I, that are involved in mediating cellular sensitivity to camptothecin. To this end, we have isolated eighteen mutants that are sensitive to camptothecin (sca) in the filamentous fungus Aspergillus nidulans and characterised one of them, sca299. The mutant sca299 is hypersensitive to camptothecin, and sensitive to several different mutagenic agents and to actinomycin D. Using temperature-sensitive mutations in genes that are known to regulate the cell cycle, we showed that the camptothecin sensitivity of the mutant sca299 is not affected by a mitotic block. The abnormal nuclear morphology observed in the sca299 mutant strain suggests that the germlings might be undergoing mitosis in the presence of unrepaired DNA damage, which would result in mitotic catastrophe. The hypersensitivity of the sca299 mutant to camptothecin does not result from elevated levels of topoisomerase I mRNA or from alterations in enzyme activity. Using DNA-mediated complementation of the sca299 mutant phenotype, the scaA+ gene was cloned. This gene encodes a 594-amino acid product; moderate structural similarity suggests that the scaA gene product may be related to the human nibrin gene which encodes a product involved in DNA double-strand break repair. Strains disrupted in the scaA gene were sensitive to the anti-topoisomerase I agent berberine, the DNA cross-linking agents mitomycin C and cis-platinum, and also to t-butyl hydroperoxide, which is an inducer of oxidative stress.",
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AU - Dani, M. A C

AU - Goldman, M. H S

AU - Morris, N. R.

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