دورية أكاديمية
Mutation P732L in human DNA topoisomerase IIbeta abolishes DNA cleavage in the presence of calcium and confers drug resistance.
| العنوان: | Mutation P732L in human DNA topoisomerase IIbeta abolishes DNA cleavage in the presence of calcium and confers drug resistance. |
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| المؤلفون: | Leontiou C; Institute for Cell and Molecular Bioscience, The Medical School, University of Newcastle, Newcastle upon Tyne, NE2 4HH, UK., Lakey JH, Lightowlers R, Turnbull RM, Austin CA |
| المصدر: | Molecular pharmacology [Mol Pharmacol] 2006 Jan; Vol. 69 (1), pp. 130-9. Date of Electronic Publication: 2005 Oct 20. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Pharmacology and Experimental Therapeutics Country of Publication: United States NLM ID: 0035623 Publication Model: Print-Electronic Cited Medium: Print ISSN: 0026-895X (Print) Linking ISSN: 0026895X NLM ISO Abbreviation: Mol Pharmacol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Bethesda, MD : American Society for Pharmacology and Experimental Therapeutics |
| مواضيع طبية MeSH: | Mutation*, Calcium/*metabolism , DNA/*metabolism , DNA Topoisomerases, Type II/*genetics , DNA Topoisomerases, Type II/*metabolism , DNA-Binding Proteins/*genetics , DNA-Binding Proteins/*metabolism, Amino Acid Sequence ; Amsacrine/pharmacology ; Antineoplastic Agents/pharmacology ; DNA Topoisomerases, Type II/chemistry ; DNA-Binding Proteins/chemistry ; Drug Resistance, Neoplasm ; Humans ; Magnesium/metabolism ; Molecular Sequence Data ; Plasmids ; Sequence Homology, Amino Acid ; Surface Plasmon Resonance |
| مستخلص: | The anti cancer drug methyl N-(4'-(9-acridinylamino)-3-methoxy-phenyl) methane sulfonamide (mAMSA) targets human DNA topoisomerase IIbeta. We report here the first selection with mAMSA of resistant human topoisomerase IIbeta. Random mutagenesis of human DNA topoisomerase IIbeta cDNA, followed by selection in yeast for resistance to mAMSA, identified betaP732L. This mutant was 10-fold less sensitive to mAMSA and cross-resistant to other chemotherapeutic agents such as etoposide, ellipticine, methyl N-(4'-(9-acridinylamino)-2-methoxy-phenyl) carbamate hydrochloride (mAMCA), methyl N-(4'-(9-acridinylamino)-phenyl) carbamate hydrochloride (AMCA), and doxorubicin. betaP732L is functional but has reduced strand passage activities and altered DNA binding compared with the wild-type protein. It has drastically altered cleavage properties compared with the wild-type enzyme. It cleaved a 40-base pair (bp) DNA substrate in the presence of magnesium but at positions different from that of the wild-type protein. More striking is that betaP732L was unable to cleave the 40-bp DNA substrate, a 500-bp linear substrate, or a 4.3-kilobase supercoiled substrate in the presence of calcium ions. This is the first report of a topoisomerase II mutation abolishing the ability of calcium to support DNA cleavage. This provides evidence for metal ion requirement for the phosphoryltransfer reaction of topoisomerase II and a possible mechanism for drug resistance. |
| معلومات مُعتمدة: | United Kingdom Wellcome Trust |
| المشرفين على المادة: | 0 (Antineoplastic Agents) 0 (DNA-Binding Proteins) 00DPD30SOY (Amsacrine) 9007-49-2 (DNA) EC 5.99.1.3 (DNA Topoisomerases, Type II) I38ZP9992A (Magnesium) SY7Q814VUP (Calcium) |
| تواريخ الأحداث: | Date Created: 20051022 Date Completed: 20060207 Latest Revision: 20171116 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1124/mol.105.015933 |
| PMID: | 16239602 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 0026-895X |
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| DOI: | 10.1124/mol.105.015933 |