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Dahm R.,Medical University of Vienna | Dahm R.,University of Padua | Dahm R.,Institute of Molecular Biology gGmbH IMB | Quinlan R.A.,Durham University | And 2 more authors.
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2011

The eye lens is avascular, deriving nutrients from the aqueous and vitreous humours. It is, however, unclear which mechanisms mediate the transfer of solutes between these humours and the lens' fibre cells (FCs). In this review, we integrate the published data with the previously unpublished ultrastructural, dye loading and magnetic resonance imaging results. The picture emerging is that solute transfer between the humours and the fibre mass is determined by four processes: (i) paracellular transport of ions, water and small molecules along the intercellular spaces between epithelial and FCs, driven by Na+-leak conductance; (ii) membrane transport of such solutes from the intercellular spaces into the fibre cytoplasm by specific carriers and transporters; (iii) gap-junctional coupling mediating solute flux between superficial and deeper fibres, Na+/K+-ATPase-driven efflux of waste products in the equator, and electrical coupling of fibres; and (iv) transcellular transfer via caveoli and coated vesicles for the uptake of macromolecules and cholesterol. There is evidence that the Na+-driven influx of solutes occurs via paracellular and membrane transport and the Na+/K+-ATPase-driven efflux of waste products via gap junctions. This micro-circulation is likely restricted to the superficial cortex and nearly absent beyond the zone of organelle loss, forming a solute exchange barrier in the lens. © 2011 The Royal Society.


Silva S.,Copenhagen University | Silva S.,University of Seville | Altmannova V.,Masaryk University | Luke-Glaser S.,Institute of Molecular Biology gGmbH IMB | And 9 more authors.
Genes and Development | Year: 2016

Mph1 is a member of the conserved FANCM family of DNA motor proteins that play key roles in genome maintenance processes underlying Fanconi anemia, a cancer predisposition syndrome in humans. Here, we identify Mte1 as a novel interactor of the Mph1 helicase in Saccharomyces cerevisiae. In vitro, Mte1 (Mph1-associated telomere maintenance protein 1) binds directly to DNA with a preference for branched molecules such as D loops and fork structures. In addition, Mte1 stimulates the helicase and fork regression activities of Mph1 while inhibiting the ability of Mph1 to dissociate recombination intermediates. Deletion of MTE1 reduces crossover recombination and suppresses the sensitivity of mph1Δ mutant cells to replication stress. Mph1 and Mte1 interdependently colocalize atDNAdamage-induced foci and dysfunctional telomeres, and MTE1 deletion results in elongated telomeres. Taken together, our data indicate that Mte1 plays a role in regulation of crossover recombination, response to replication stress, and telomere maintenance. © 2016 Silva et al.


Maruyama E.O.,Tohoku University | Hori T.,Graduate University for Advanced Studies | Tanabe H.,Graduate University for Advanced Studies | Kitamura H.,Tohoku University | And 8 more authors.
Journal of Cell Science | Year: 2012

The spatial organization of chromatin in the nucleus contributes to genome function and is altered during the differentiation of normal and tumorigenic cells. Although nuclear actin-related proteins (Arps) have roles in the local alteration of chromatin structure, it is unclear whether they are involved in the spatial positioning of chromatin. In the interphase nucleus of vertebrate cells, gene-dense and gene-poor chromosome territories (CTs) are located in the center and periphery, respectively. We analyzed chicken DT40 cells in which Arp6 had been knocked out conditionally, and showed that the radial distribution of CTs was impaired in these knockout cells. Arp6 is an essential component of the SRCAP chromatin remodeling complex, which deposits the histone variant H2A.Z into chromatin. The redistribution of CTs was also observed in H2A.Z-deficient cells for gene-rich microchromosomes, but to lesser extent for gene-poor macrochromosomes. These results indicate that Arp6 and H2A.Z contribute to the radial distribution of CTs through different mechanisms. Microarray analysis suggested that the localization of chromatin to the nuclear periphery per se is insufficient for the repression of most genes. © 2012. Published by The Company of Biologists Ltd.


Montavon T.,Max Planck Institute of Immunobiology and Epigenetics | Soshnikova N.,Institute of Molecular Biology gGmbH IMB
Seminars in Cell and Developmental Biology | Year: 2014

Hox genes are critical regulators of embryonic development in bilaterian animals. They exhibit a unique mode of transcriptional regulation where the position of the genes along the chromosome corresponds to the time and place of their expression during development. The sequential temporal activation of these genes in the primitive streak helps determining their subsequent pattern of expression along the anterior-posterior axis of the embryo, yet the precise correspondence between these two collinear processes is not fully understood. In addition, vertebrate Hox genes evolved similar modes of regulation along secondary body axes, such as the developing limbs. We review the current understanding of the mechanisms operating during activation, maintenance and silencing of Hox gene expression in these various contexts, and discuss the evolutionary significance of their genomic organization. © 2014 Elsevier Ltd.


PubMed | Institute of Molecular Biology gGmbH IMB and Max Planck Institute of Immunobiology and Epigenetics
Type: | Journal: Seminars in cell & developmental biology | Year: 2014

Hox genes are critical regulators of embryonic development in bilaterian animals. They exhibit a unique mode of transcriptional regulation where the position of the genes along the chromosome corresponds to the time and place of their expression during development. The sequential temporal activation of these genes in the primitive streak helps determining their subsequent pattern of expression along the anterior-posterior axis of the embryo, yet the precise correspondence between these two collinear processes is not fully understood. In addition, vertebrate Hox genes evolved similar modes of regulation along secondary body axes, such as the developing limbs. We review the current understanding of the mechanisms operating during activation, maintenance and silencing of Hox gene expression in these various contexts, and discuss the evolutionary significance of their genomic organization.


Coelho M.B.,University of Cambridge | Attig J.,University College London | Attig J.,University of Cambridge | Bellora N.,University Pompeu Fabra | And 11 more authors.
EMBO Journal | Year: 2015

Matrin3 is an RNA- and DNA-binding nuclear matrix protein found to be associated with neural and muscular degenerative diseases. A number of possible functions of Matrin3 have been suggested, but no widespread role in RNA metabolism has yet been clearly demonstrated. We identified Matrin3 by its interaction with the second RRM domain of the splicing regulator PTB. Using a combination of RNAi knockdown, transcriptome profiling and iCLIP, we find that Matrin3 is a regulator of hundreds of alternative splicing events, principally acting as a splicing repressor with only a small proportion of targeted events being co-regulated by PTB. In contrast to other splicing regulators, Matrin3 binds to an extended region within repressed exons and flanking introns with no sharply defined peaks. The identification of this clear molecular function of Matrin3 should help to clarify the molecular pathology of ALS and other diseases caused by mutations of Matrin3. Synopsis Matrin3 is a nuclear matrix protein that was recently linked to neurodegeneration. This study finds Matrin3 to be a splicing repressor that modulates hundreds of alternative splice events, offering possible insight on disease onset. Nuclear matrix protein Matrin3 uses a GILGPPP motif to dock onto the RRM2 domain of splice regulator PTB. Transcriptome-wide profiling shows changes in hundreds of alternative splicing events (ASE) upon Matrin3 knockdown; only a subset of these are also regulated by PTB. Unlike other splicing regulators, Matrin3 binds to extended regions within and around repressed exons. Matrin3 requires its RRMs and the GILGPPP motif to regulate splicing of both PTB-dependent and PTB-independent ASEs, suggesting possible crosstalk with other RRM-containing splice factors. The finding that Matrin3 plays a role in controlling alternative splicing may help understand the etiology of Matrin3-associated pathologies. Matrin3 is a nuclear matrix protein that was recently linked to neurodegeneration. This study finds Matrin3 to be a splicing repressor that modulates hundreds of alternative splice events, offering possible insight on disease onset. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.


Villa M.,University of Milan Bicocca | Cassani C.,University of Milan Bicocca | Gobbini E.,University of Milan Bicocca | Bonetti D.,Institute of Molecular Biology gGmbH IMB | Longhese M.P.,University of Milan Bicocca
Cellular and Molecular Life Sciences | Year: 2016

DNA double-strand breaks (DSBs) are a nasty form of damage that needs to be repaired to ensure genome stability. The DSB ends can undergo a strand-biased nucleolytic processing (resection) to generate 3′-ended single-stranded DNA (ssDNA) that channels DSB repair into homologous recombination. Generation of ssDNA also triggers the activation of the DNA damage checkpoint, which couples cell cycle progression with DSB repair. The checkpoint response is intimately linked to DSB resection, as some checkpoint proteins regulate the resection process. The present review will highlight recent works on the mechanism and regulation of DSB resection and its interplays with checkpoint activation/inactivation in budding yeast. © 2016 Springer International Publishing


PubMed | University of Milan Bicocca and Institute of Molecular Biology gGmbH IMB
Type: Journal Article | Journal: Cellular and molecular life sciences : CMLS | Year: 2016

DNA double-strand breaks (DSBs) are a nasty form of damage that needs to be repaired to ensure genome stability. The DSB ends can undergo a strand-biased nucleolytic processing (resection) to generate 3-ended single-stranded DNA (ssDNA) that channels DSB repair into homologous recombination. Generation of ssDNA also triggers the activation of the DNA damage checkpoint, which couples cell cycle progression with DSB repair. The checkpoint response is intimately linked to DSB resection, as some checkpoint proteins regulate the resection process. The present review will highlight recent works on the mechanism and regulation of DSB resection and its interplays with checkpoint activation/inactivation in budding yeast.

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