The Analysis of Mutant Alleles of Different Strength Reveals Multiple Functions of Topoisomerase 2 in Regulation of Chromosome Structure

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Type II topoisomerases (Topo II) are enzymes that disentangle DNA molecules during essential cellular processes such as DNA replication, chromosome condensation and mitotic cell division. Topo II is a major component of mitotic chromosomes and it is a well known target for cancer chemotherapy. Topo II inhibitors block the Topo II enzymatic activity leading to extensive DNA damage, which ultimately kills the cancer cell. Thus, investigating the role of Topo II in the assembly and structural maintenance of chromosomes is not only relevant to understand chromosome biology but might also have a translational impact on cancer therapy. Here we used Drosophila as model system to analyze the effect of Topo II depletion on chromosome stability. We show that the chromosomal phenotypes of mutant flies vary with the amount of residual Topo II, ranging from site-specific chromosome breaks, variations in chromosome number (aneuploidy and poliploidy) and dramatic defects in chromosome morphology. The chromosomal phenotypes observed in flies recapitulate all phenotypes seen in Topo II-depleted vertebrate chromosomes, reconciling the phenotypic discrepancies reported in previous studies. In addition, our finding that the Topo II dependent phenotypes vary with the residual amount of the enzyme provides useful information on the possible outcome of cancer therapy with Topo II inhibitors.

Vyšlo v časopise: The Analysis of Mutant Alleles of Different Strength Reveals Multiple Functions of Topoisomerase 2 in Regulation of Chromosome Structure. PLoS Genet 10(10): e32767. doi:10.1371/journal.pgen.1004739
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004739

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