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  • 1
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    Defects in optineurin- and myosin VI-mediated cellular trafficking in amyotrophic lateral sclerosis (2015)
    Oxford University Press
    Details
    Publication Date: 2015-06-09
    Description: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder primarily affecting motor neurons. Mutations in optineurin cause a small proportion of familial ALS cases, and wild-type (WT) optineurin is misfolded and forms inclusions in sporadic ALS patient motor neurons. However, it is unknown how optineurin mutation or misfolding leads to ALS. Optineurin acts an adaptor protein connecting the molecular motor myosin VI to secretory vesicles and autophagosomes. Here, we demonstrate that ALS-linked mutations p.Q398X and p.E478G disrupt the association of optineurin with myosin VI, leading to an abnormal diffuse cytoplasmic distribution, inhibition of secretory protein trafficking, endoplasmic reticulum (ER) stress and Golgi fragmentation in motor neuron-like NSC-34 cells. We also provide further insight into the role of optineurin as an autophagy receptor. WT optineurin associated with lysosomes and promoted autophagosome fusion to lysosomes in neuronal cells, implying that it mediates trafficking of lysosomes during autophagy in association with myosin VI. However, either expression of ALS mutant optineurin or small interfering RNA-mediated knockdown of endogenous optineurin blocked lysosome fusion to autophagosomes, resulting in autophagosome accumulation. Together these results indicate that ALS-linked mutations in optineurin disrupt myosin VI-mediated intracellular trafficking processes. In addition, in control human patient tissues, optineurin displayed its normal vesicular localization, but in sporadic ALS patient tissues, vesicles were present in a significantly decreased proportion of motor neurons. Optineurin binding to myosin VI was also decreased in tissue lysates from sporadic ALS spinal cords. This study therefore links several previously described pathological mechanisms in ALS, including defects in autophagy, fragmentation of the Golgi and induction of ER stress, to disruption of optineurin function. These findings also indicate that optineurin–myosin VI dysfunction is a common feature of both sporadic and familial ALS.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 2
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    Increased STAG2 dosage defines a novel cohesinopathy with intellectual disability and behavioral problems (2015)
    Oxford University Press
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    Publication Date: 2015-12-01
    Description: Next generation genomic technologies have made a significant contribution to the understanding of the genetic architecture of human neurodevelopmental disorders. Copy number variants (CNVs) play an important role in the genetics of intellectual disability (ID). For many CNVs, and copy number gains in particular, the responsible dosage-sensitive gene(s) have been hard to identify. We have collected 18 different interstitial microduplications and 1 microtriplication of Xq25. There were 15 affected individuals from 6 different families and 13 singleton cases, 28 affected males in total. The critical overlapping region involved the STAG2 gene, which codes for a subunit of the cohesin complex that regulates cohesion of sister chromatids and gene transcription. We demonstrate that STAG2 is the dosage-sensitive gene within these CNVs, as gains of STAG2 mRNA and protein dysregulate disease-relevant neuronal gene networks in cells derived from affected individuals. We also show that STAG2 gains result in increased expression of OPHN1 , a known X-chromosome ID gene. Overall, we define a novel cohesinopathy due to copy number gain of Xq25 and STAG2 in particular.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 3
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    Harnessing a previously unidentified capability of bacterial allosteric transcription factors for sensing diverse small molecules in vitro (2018)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2018
    Description: 〈p〉A plethora of bacterial allosteric transcription factors (aTFs) have been identified to sense a variety of small molecules. Introduction of a novel aTF-based approach to sense diverse small molecules in vitro will signify a broad series of detection applications. Here, we found that aTFs could interact with their nicked DNA binding sites. Building from this new finding, we designed and implemented a novel aTF-based nicked DNA template–assisted signal transduction system (aTF-NAST) by using the competition between aTFs and T4 DNA ligase to bind to the nicked DNA. This aTF-NAST could reliably and modularly transduce the signal of small molecules recognized by aTFs to the ligated DNA signal, thus enabling the small molecules to be measured via various mature and robust DNA detection methods. Coupling this aTF-NAST with three DNA detection methods, we demonstrated nine novel biosensors for the detection of an antiseptic 4-hydroxybenzoic acid, a disease marker uric acid and an antibiotic tetracycline. These biosensors show impressive sensitivity and robustness in real-life analysis, highlighting the great potential of our aTF-NAST for biosensing applications.〈/p〉
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
    Published by American Association for the Advancement of Science (AAAS)
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  • 4
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    Harnessing a previously unidentified capability of bacterial allosteric transcription factors for sensing diverse small molecules in vitro (2018)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2018-11-29
    Description: A plethora of bacterial allosteric transcription factors (aTFs) have been identified to sense a variety of small molecules. Introduction of a novel aTF-based approach to sense diverse small molecules in vitro will signify a broad series of detection applications. Here, we found that aTFs could interact with their nicked DNA binding sites. Building from this new finding, we designed and implemented a novel aTF-based nicked DNA template–assisted signal transduction system (aTF-NAST) by using the competition between aTFs and T4 DNA ligase to bind to the nicked DNA. This aTF-NAST could reliably and modularly transduce the signal of small molecules recognized by aTFs to the ligated DNA signal, thus enabling the small molecules to be measured via various mature and robust DNA detection methods. Coupling this aTF-NAST with three DNA detection methods, we demonstrated nine novel biosensors for the detection of an antiseptic 4-hydroxybenzoic acid, a disease marker uric acid and an antibiotic tetracycline. These biosensors show impressive sensitivity and robustness in real-life analysis, highlighting the great potential of our aTF-NAST for biosensing applications.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
    Published by American Association for the Advancement of Science (AAAS)
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  • 5
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    Molecular architecture of the active mitochondrial protein gate (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-09-26
    Description: Mitochondria fulfill central functions in cellular energetics, metabolism, and signaling. The outer membrane translocator complex (the TOM complex) imports most mitochondrial proteins, but its architecture is unknown. Using a cross-linking approach, we mapped the active translocator down to single amino acid residues, revealing different transport paths for preproteins through the Tom40 channel. An N-terminal segment of Tom40 passes from the cytosol through the channel to recruit chaperones from the intermembrane space that guide the transfer of hydrophobic preproteins. The translocator contains three Tom40 beta-barrel channels sandwiched between a central alpha-helical Tom22 receptor cluster and external regulatory Tom proteins. The preprotein-translocating trimeric complex exchanges with a dimeric isoform to assemble new TOM complexes. Dynamic coupling of alpha-helical receptors, beta-barrel channels, and chaperones generates a versatile machinery that transports about 1000 different proteins.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shiota, Takuya -- Imai, Kenichiro -- Qiu, Jian -- Hewitt, Victoria L -- Tan, Khershing -- Shen, Hsin-Hui -- Sakiyama, Noriyuki -- Fukasawa, Yoshinori -- Hayat, Sikander -- Kamiya, Megumi -- Elofsson, Arne -- Tomii, Kentaro -- Horton, Paul -- Wiedemann, Nils -- Pfanner, Nikolaus -- Lithgow, Trevor -- Endo, Toshiya -- New York, N.Y. -- Science. 2015 Sep 25;349(6255):1544-8. doi: 10.1126/science.aac6428.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, Victoria 3800, Australia. Department of Chemistry, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan. ; Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology, 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan. ; Institut fur Biochemie und Molekularbiologie, Universitat Freiburg, 79104 Freiburg, Germany. ; Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, Victoria 3800, Australia. ; Department of Biochemistry and Biophysics and Science for Life Laboratory, Stockholm University, Box 1031, 17121 Solna, Sweden. ; Department of Chemistry, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan. ; Institut fur Biochemie und Molekularbiologie, Universitat Freiburg, 79104 Freiburg, Germany. Centre for Biological Signalling Studies, Universitat Freiburg, 79104 Freiburg, Germany. ; Department of Chemistry, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan. Faculty of Life Sciences, Kyoto Sangyo University, Kamigamo-motoyama, Kita-ku, Kyoto 603-8555, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26404837" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Cytosol/metabolism ; Mitochondrial Membrane Transport Proteins/*chemistry/metabolism ; Molecular Chaperones ; Molecular Sequence Data ; Protein Multimerization ; Protein Structure, Secondary ; Protein Transport ; Saccharomyces cerevisiae Proteins/*chemistry/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 6
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    Efficient production of superior dumbbell-shaped DNA minimal vectors for small hairpin RNA expression (2015)
    Oxford University Press
    Details
    Publication Date: 2015-10-15
    Description: Genetic therapy holds great promise for the treatment of inherited or acquired genetic diseases; however, its breakthrough is hampered by the lack of suitable gene delivery systems. Dumbbell-shaped DNA minimal vectors represent an attractive, safe alternative to the commonly used viral vectors which are fraught with risk, but dumbbell generation appears to be costly and time-consuming. We developed a new PCR-based method for dumbbell production which comprises only two steps. First, PCR amplification of the therapeutic expression cassette using chemically modified primers to form a ready-to-ligate DNA structure; and second, a highly efficient intramolecular ligation reaction. Compared with conventional strategies, the new method produces dumbbell vectors more rapidly, with higher yields and purity, and at lower costs. In addition, such produced small hairpin RNA expressing dumbbells triggered superior target gene knockdown compared with conventionally produced dumbbells or plasmids. Our novel method is suitable for large-scale dumbbell production and can facilitate clinical applications of this vector system.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 7
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    Structural basis for suppression of hypernegative DNA supercoiling by E. coli topoisomerase I (2015)
    Oxford University Press
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    Publication Date: 2015-12-16
    Description: Escherichia coli topoisomerase I has an essential function in preventing hypernegative supercoiling of DNA. A full length structure of E. coli topoisomerase I reported here shows how the C-terminal domains bind single-stranded DNA (ssDNA) to recognize the accumulation of negative supercoils in duplex DNA. These C-terminal domains of E. coli topoisomerase I are known to interact with RNA polymerase, and two flexible linkers within the C-terminal domains may assist in the movement of the ssDNA for the rapid removal of transcription driven negative supercoils. The structure has also unveiled for the first time how the 4-Cys zinc ribbon domain and zinc ribbon-like domain bind ssDNA with primarily -stacking interactions. This novel structure, in combination with new biochemical data, provides important insights into the mechanism of genome regulation by type IA topoisomerases that is essential for life, as well as the structures of homologous type IA TOP3α and TOP3β from higher eukaryotes that also have multiple 4-Cys zinc ribbon domains required for their physiological functions.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 8
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    The Iwasawa Main Conjecture for constant ordinary abelian varieties over function fields (2016)
    Oxford University Press
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    Publication Date: 2016-06-11
    Description: We study a geometric analogue of the Iwasawa Main Conjecture for constant ordinary abelian varieties over $\mathbb {Z}_p^d$ -extensions of function fields ramifying at a finite set of places.
    Print ISSN: 0024-6115
    Electronic ISSN: 1460-244X
    Topics: Mathematics
    Published by Oxford University Press
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  • 9
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    4DGenome: a comprehensive database of chromatin interactions (2016)
    Oxford University Press
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    Publication Date: 2016-09-02
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Published by Oxford University Press
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  • 10
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    Recombinase and translesion DNA polymerase decrease the speed of replication fork progression during the DNA damage response in Escherichia coli cells (2015)
    Oxford University Press
    Details
    Publication Date: 2015-02-18
    Description: The SOS response is a DNA damage response pathway that serves as a general safeguard of genome integrity in bacteria. Extensive studies of the SOS response in Escherichia coli have contributed to establishing the key concepts of cellular responses to DNA damage. However, how the SOS response impacts on the dynamics of DNA replication fork movement remains unknown. We found that inducing the SOS response decreases the mean speed of individual replication forks by 30–50% in E. coli cells, leading to a 20–30% reduction in overall DNA synthesis. dinB and recA belong to a group of genes that are upregulated during the SOS response, and encode the highly conserved proteins DinB (also known as DNA polymerase IV) and RecA, which, respectively, specializes in translesion DNA synthesis and functions as the central recombination protein. Both genes were independently responsible for the SOS-dependent slowdown of replication fork progression. Furthermore, fork speed was reduced when each gene was ectopically expressed in SOS-uninduced cells to the levels at which they are expressed in SOS-induced cells. These results clearly indicate that the increased expression of dinB and recA performs a novel role in restraining the progression of an unperturbed replication fork during the SOS response.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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