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The Broken MLL Gene Is Frequently Located Outside the Inherent Chromosome Territory in Human Lymphoid Cells Treated with DNA Topoisomerase II Poison Etoposideстатья
Статья опубликована в высокорейтинговом журнале
Информация о цитировании статьи получена из
Web of Science,
Scopus
Статья опубликована в журнале из списка Web of Science и/или Scopus
Дата последнего поиска статьи во внешних источниках: 4 февраля 2014 г.
- Авторы: Glukhov S.I., Rubtsov M.A., Alexeyevsky D.A., Alexeevski A.V., Razin S.V., Iarovaia O.V.
- Журнал: PLoS ONE
- Том: 8
- Номер: 9
- Год издания: 2013
- Издательство: Public Library of Science
- Местоположение издательства: United States
- Первая страница: e75871
- DOI: 10.1371/journal.pone.0075871
- Аннотация: The mixed lineage leukaemia (MLL) gene is frequently rearranged in secondary leukaemias, in which it could fuse to a variety of different partners. Breakage in the MLL gene preferentially occurs within a ~8 kb region that possesses a strong DNA topoisomerase II cleavage site. It has been proposed that DNA topoisomerase II-mediated DNA cleavage within this and other regions triggers translocations that occur due to incorrect joining of broken DNA ends. To further clarify a possible mechanism for MLL rearrangements, we analysed the frequency of MLL cleavage in cells exposed to etoposide, a DNA topoisomerase II poison commonly used as an anticancer drug, and positioning of the broken 3’-end of the MLL gene in respect to inherent chromosomal territories. It was demonstrated that exposure of human Jurkat cells to etoposide resulted in frequent cleavage of MLL genes. Using MLL-specific break-apart probes we visualised cleaved MLL genes in ~17% of nuclei. Using confocal microscopy and 3D modelling, we demonstrated that in cells treated with etoposide and cultivated for 1 h under normal conditions, ~9% of the broken MLL alleles were present outside the chromosome 11 territory, whereas in both control cells and cells inspected immediately after etoposide treatment, virtually all MLL alleles were present within the chromosomal territory. The data are discussed in the framework of the “breakage first” model of juxtaposing translocation partners. We propose that in the course of repairing DNA topoisomerase II-mediated DNA lesions (removal of stalled DNA topoisomerase II complexes and non-homologous end joining), DNA ends acquire additional mobility, which allows the meeting and incorrect joining of translocation partners.
- Добавил в систему: Разин Сергей Владимирович