4-quinolone antibiotics : Positive genotoxic screening tests despite an apparent lack of mutation induction

The effects of different 4-quinolone antibiotic derivatives (4-Qs) in a number of short-term tests commonly employed for the evaluation of genetic toxicity were studied. Incorporation of [3H]thymidine into mitogen-stimulated peripheral blood lymphocytes was strongly enhanced at a low concentration (1.56 μg/ml) for most of the tested 4-Qs, whereas DNA strand breakage in lymphoblastoid cells was evident only for ciprofloxacin (10 μg/ml and upwards), ofloxacin (80 μg/ml) and norfloxacin (160 μg/ml). Ciphrofloxacin induced a significant amount of unscheduled DNA synthesis, but was found to be negative in a shuttle vector plasmid mutation test. Ciprofloxacin (80 μg/ml) did not inhibit enzymes involved in the early steps of pyrimidine biosynthesis. Cell growth was slightly depressed at a concentration of 20 μg/ml, becoming marked at 80 μg/ml. In conculsion, this study seeks to contribute to an improved evaluation of genotoxic screening test data, by focuding attention on the conflicting effects imposed by the 4-Qs on a battery of such tests

Correction: Microtubule-induced nuclear envelope fluctuations control chromatin dynamics in Drosophila

International audienceNuclear shape is different in stem cells and differentiated cells and reflects important changes in the mechanics of the nuclear envelope (NE). The current framework emphasizes the key role of the nuclear lamina in nuclear mechanics and its alterations in disease. Whether active stress controls nuclear deformations and how this stress interplays with properties of the NE to control NE dynamics is unclear. We address this in the early Drosophila embryo, in which profound changes in NE shape parallel the transcriptional activation of the zygotic genome. We show that microtubule (MT) polymerization events produce the elementary forces necessary for NE dynamics. Moreover, large-scale NE deformations associated with groove formation require concentration of MT polymerization in bundles organized by Dynein. However, MT bundles cannot produce grooves when the farnesylated inner nuclear membrane protein Kugelkern (Kuk) is absent. Although it increases stiffness of the NE, Kuk also stabilizes NE deformations emerging from the collective effect of MT polymerization forces concentrated in bundles. Finally, we report that MT-induced NE deformations control the dynamics of chromatin and its organization at steady state. Thus, the NE is a dynamic organelle, fluctuations of which increase chromatin dynamics. We propose that such mechanical regulation of chromatin dynamics by MTs might be important for gene regulation

Microtubule-induced nuclear envelope fluctuations control chromatin dynamics in Drosophila embryos

International audienceNuclear shape is different in stem cells and differentiated cells and reflects important changes in the mechanics of the nuclear envelope (NE). The current framework emphasizes the key role of the nuclear lamina in nuclear mechanics and its alterations in disease 1, 2 . Whether active stress controls nuclear deformations and how this stress interplays with properties of the NE to control NE dynamics is unclear. We address this in the early Drosophila embryo, where profound changes in NE shape parallel the transcriptional activation of the zygotic genome. We show that microtubule (MT) polymerization events produce the elementary forces necessary for NE dynamics. Moreover, large-scale NE-deformations associated with groove formation require concentration of microtubule polymerization in bundles organized by Dynein. However, MT bundles cannot produce grooves when the farnesylated inner nuclear membrane protein Charleston/Kugelkern (Char/Kuk) is absent 3, 4 . Although it increases stiffness of the NE, Char/Kuk also stabilizes NE deformations emerging from the collective effect of MT polymerization forces concentrated in bundles. Finally we report that MT induced NE deformations control the dynamics of the chromatin and its organization at steady state. Thus, the NE is a dynamic organelle, whose fluctuations increase chromatin dynamics. We propose that such mechanical regulation of chromatin dynamics by MT may be important for gene regulation

Microtubule-induced nuclear envelope fluctuations control chromatin dynamics in Drosophila embryos

International audienceNuclear shape is different in stem cells and differentiated cells and reflects important changes in the mechanics of the nuclear envelope (NE). The current framework emphasizes the key role of the nuclear lamina in nuclear mechanics and its alterations in disease. Whether active stress controls nuclear deformations and how this stress interplays with properties of the NE to control NE dynamics is unclear. We address this in the early Drosophila embryo, in which profound changes in NE shape parallel the transcriptional activation of the zygotic genome. We show that microtubule (MT) polymerization events produce the elementary forces necessary for NE dynamics. Moreover, large-scale NE deformations associated with groove formation require concentration of MT polymerization in bundles organized by Dynein. However, MT bundles cannot produce grooves when the farnesylated inner nuclear membrane protein Kugelkern (Kuk) is absent. Although it increases stiffness of the NE, Kuk also stabilizes NE deformations emerging from the collective effect of MT polymerization forces concentrated in bundles. Finally, we report that MT-induced NE deformations control the dynamics of chromatin and its organization at steady state. Thus, the NE is a dynamic organelle, fluctuations of which increase chromatin dynamics. We propose that such mechanical regulation of chromatin dynamics by MTs might be important for gene regulation

Septins promote F-actin ring formation by crosslinking actin filaments into curved bundles

International audienceAnimal cell cytokinesis requires a contractile ring of crosslinked actin filaments and myosin motors. How contractile rings form and are stabilized in dividing cells remains unclear. We address this problem by focusing on septins, highly conserved proteins in eukaryotes whose precise contribution to cytokinesis remains elusive. We use the cleavage of the Drosophila melanogaster embryo as a model system, where contractile actin rings drive constriction of invaginating membranes to produce an epithelium in a manner akin to cell division. In vivo functional studies show that septins are required for generating curved and tightly packed actin filament networks. In vitro reconstitution assays show that septins alone bundle actin filaments into rings, accounting for the defects in actin ring formation in septin mutants. The bundling and bending activities are conserved for human septins, and highlight unique functions of septins in the organization of contractile actomyosin rings