Reciprocal DNA topoisomerase II cleavage events at 5'-TATTA-3' sequences in MLL and AF-9 create homologous single-stranded overhangs that anneal to form der(11) and der(9) genomic breakpoint junctions in treatment-related AML without further processing
| Autor: | Diana J. Slater, Charles Saginario, Ian A. Blair, Neil Osheroff, Eric F. Rappaport, Maureen D. Megonigal, Eva Hilgenfeld, Carolyn A. Felix, Ryan J. Whitmarsh, Mingli Liu, Thomas Ried, Turid Knutsen, Nai-Kong V. Cheung, Martin Carroll, Ya Zhuo |
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| Rok vydání: | 2003 |
| Předmět: |
Male
Cancer Research Adolescent DNA damage Molecular Sequence Data Biology medicine.disease_cause Cleavage (embryo) Translocation Genetic hemic and lymphatic diseases Proto-Oncogenes Genetics medicine Humans Molecular Biology Transcription factor Etoposide In Situ Hybridization Fluorescence Recombination Genetic Topoisomerase Breakpoint Intron Nuclear Proteins Histone-Lysine N-Methyltransferase Molecular biology DNA-Binding Proteins Leukemia Myeloid Acute DNA Topoisomerases Type II biology.protein Carcinogenesis Protein Processing Post-Translational Myeloid-Lymphoid Leukemia Protein medicine.drug Transcription Factors |
| Zdroj: | Oncogene. 22(52) |
| ISSN: | 0950-9232 |
| Popis: | Few t(9;11) translocations in DNA topoisomerase II inhibitor-related leukemias have been studied in detail and the DNA damage mechanism remains controversial. We characterized the der(11) and der(9) genomic breakpoint junctions in a case of AML following etoposide and doxorubicin. Etoposide-, etoposide metabolite- and doxorubicin-induced DNA topoisomerase II cleavage was examined in normal homologues of the MLL and AF-9 breakpoint sequences using an in vitro assay. Induction of DNA topoisomerase II cleavage complexes in CEM and K562 cell lines was investigated using an in vivo complex of enzyme assay. The translocation occurred between identical 5'-TATTA-3' sequences in MLL intron 8 and AF-9 intron 5 without the gain or loss of bases. The 5'-TATTA-3' sequences were reciprocally cleaved by DNA topoisomerase II in the presence of etoposide, etoposide catechol or etoposide quinone, creating homologous 4-base 5' overhangs that would anneal to form both breakpoint junctions without any processing. der(11) and der(4) translocation breakpoints in a treatment-related ALL at the same site in MLL are consistent with a damage hotspot. Etoposide and both etoposide metabolites induced DNA topoisomerase II cleavage complexes in the hematopoietic cell lines. These results favor the model in which the chromosomal breakage leading to MLL translocations in DNA topoisomerase II inhibitor-related leukemias is a consequence of DNA topoisomerase II cleavage. |
| Databáze: | OpenAIRE |
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