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  • 1
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    A ubiquitylation site in Cockayne syndrome B required for repair of oxidative DNA damage, but not for transcription-coupled nucleotide excision repair (2016)
    Oxford University Press
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    Publication Date: 2016-06-21
    Description: Cockayne syndrome B (CSB), best known for its role in transcription-coupled nucleotide excision repair (TC-NER), contains a ubiquitin-binding domain (UBD), but the functional connection between protein ubiquitylation and this UBD remains unclear. Here, we show that CSB is regulated via site-specific ubiquitylation. Mass spectrometry analysis of CSB identified lysine (K) 991 as a ubiquitylation site. Intriguingly, mutation of this residue (K991R) does not affect CSB's catalytic activity or protein stability, but greatly affects genome stability, even in the absence of induced DNA damage. Moreover, cells expressing CSB K991R are sensitive to oxidative DNA damage, but proficient for TC-NER. K991 becomes ubiquitylated upon oxidative DNA damage, and while CSB K991R is recruited normally to such damage, it fails to dissociate in a timely manner, suggesting a requirement for K991 ubiquitylation in CSB activation. Interestingly, deletion of CSB's UBD gives rise to oxidative damage sensitivity as well, while CSB UBD and CSB K991R affects expression of overlapping groups of genes, further indicating a functional connection. Together, these results shed new light on the regulation of CSB, with K991R representing an important separation-of-function-mutation in this multi-functional protein.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 2
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    PINK1 rendered temperature sensitive by disease-associated and engineered mutations (2013)
    Oxford University Press
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    Publication Date: 2013-06-07
    Description: Mutations in Parkin or PINK1 are the most common cause of recessively inherited parkinsonism. Parkin and PINK1 function in a conserved mitochondrial quality control pathway, in which PINK1, a putative mitochondrial kinase, directs Parkin, a cytosolic E3 ubiquitin ligase, selectively to dysfunctional mitochondria to promote their isolation, immobilization and degradation by macroautophagy (hereafter, mitophagy). As Parkin recruitment to mitochondria is robustly induced by PINK1 expression on the outer mitochondrial membrane, Parkin recruitment to mitochondria was used as an assay for PINK1 function. Unexpectedly, mutation of serine residues within the activation segment of PINK1 uncovered a temperature-sensitive variant of PINK1 (tsPINK1). tsPINK1 allowed for the first time the disassociation of PINK1 activity from its expression and localization. Additionally, extensive mutagenesis identified three disease-associated variants in the activation segment and one in an α-helix N-terminal to kinase domain (Q126P) that are similarly thermally labile, suggesting that their activity could be restored post-translationally (e.g. by reducing the temperature or by a chemical or pharmacologic chaperone). Together, these findings suggest that tsPINK1 may represent a valuable tool for the analysis of the PINK1/Parkin pathway in human cells; additionally, as the serine residue promoting thermal lability is conserved among Mus musculus , Danio rerio , Drosophila melanogaster and Caenorhabditis elegans , it may serve as the basis for developing other temperature-sensitive models for the study of recessive parkinsonism and mitophagy. Finally, these results suggest that PINK1 kinase function could be restored for a subset of patients with PINK1 mutations, and perhaps alter the course of their disease.
    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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    On the nature of magnetic turbulence in rotating, shearing flows (2016)
    Oxford University Press
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    Publication Date: 2016-01-07
    Description: The local properties of turbulence driven by the magnetorotational instability (MRI) in rotating, shearing flows are studied in the framework of a shearing-box model. Based on numerical simulations, we propose that the MRI-driven turbulence comprises two components: the large-scale shear-aligned strong magnetic field and the small-scale fluctuations resembling magnetohydrodynamic (MHD) turbulence. The energy spectrum of the large-scale component is close to k –2 , whereas the spectrum of the small-scale component agrees with the spectrum of strong MHD turbulence k –3/2 . While the spectrum of the fluctuations is universal, the outer-scale characteristics of the turbulence are not; they depend on the parameters of the system, such as the net magnetic flux. However, there is remarkable universality among the allowed turbulent states – their intensity v 0 and their outer scale 0 satisfy the balance condition v 0 / 0 ~ d/dln r , where d/dln r is the local orbital shearing rate of the flow. Finally, we find no sustained dynamo action in the Pm = 1 zero net-flux case for Reynolds numbers as high as 45 000, casting doubts on the existence of an MRI dynamo in the Pm ≤ 1 regime.
    Print ISSN: 1745-3925
    Electronic ISSN: 1745-3933
    Topics: Physics
    Published by Oxford University Press
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  • 4
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    Sequence Analysis and Characterization of Active Human Alu Subfamilies Based on the 1000 Genomes Pilot Project (2015)
    Oxford University Press
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    Publication Date: 2015-09-24
    Description: The goal of the 1000 Genomes Consortium is to characterize human genome structural variation (SV), including forms of copy number variations such as deletions, duplications, and insertions. Mobile element insertions, particularly Alu elements, are major contributors to genomic SV among humans. During the pilot phase of the project we experimentally validated 645 (611 intergenic and 34 exon targeted) polymorphic "young" Alu insertion events, absent from the human reference genome. Here, we report high resolution sequencing of 343 (322 unique) recent Alu insertion events, along with their respective target site duplications, precise genomic breakpoint coordinates, subfamily assignment, percent divergence, and estimated A-rich tail lengths. All the sequenced Alu loci were derived from the Alu Y lineage with no evidence of retrotransposition activity involving older Alu families (e.g., Alu J and Alu S). Alu Ya5 is currently the most active Alu subfamily in the human lineage, followed by Alu Yb8, and many others including three newly identified subfamilies we have termed Alu Yb7a3, Alu Yb8b1, and Alu Ya4a1. This report provides the structural details of 322 unique Alu variants from individual human genomes collectively adding about 100 kb of genomic variation. Many Alu subfamilies are currently active in human populations, including a surprising level of Alu Y retrotransposition. Human Alu subfamilies exhibit continuous evolution with potential drivers sprouting new Alu lineages.
    Electronic ISSN: 1759-6653
    Topics: Biology
    Published by Oxford University Press
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  • 5
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    Mitochondrial nucleoid interacting proteins support mitochondrial protein synthesis (2012)
    Oxford University Press
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    Publication Date: 2012-07-22
    Description: Mitochondrial ribosomes and translation factors co-purify with mitochondrial nucleoids of human cells, based on affinity protein purification of tagged mitochondrial DNA binding proteins. Among the most frequently identified proteins were ATAD3 and prohibitin, which have been identified previously as nucleoid components, using a variety of methods. Both proteins are demonstrated to be required for mitochondrial protein synthesis in human cultured cells, and the major binding partner of ATAD3 is the mitochondrial ribosome. Altered ATAD3 expression also perturbs mtDNA maintenance and replication. These findings suggest an intimate association between nucleoids and the machinery of protein synthesis in mitochondria. ATAD3 and prohibitin are tightly associated with the mitochondrial membranes and so we propose that they support nucleic acid complexes at the inner membrane of the mitochondrion.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 6
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    Human C4orf14 interacts with the mitochondrial nucleoid and is involved in the biogenesis of the small mitochondrial ribosomal subunit (2012)
    Oxford University Press
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    Publication Date: 2012-07-22
    Description: The bacterial homologue of C4orf14, YqeH, has been linked to assembly of the small ribosomal subunit. Here, recombinant C4orf14 isolated from human cells, co-purified with the small, 28S subunit of the mitochondrial ribosome and the endogenous protein co-fractionated with the 28S subunit in sucrose gradients. Gene silencing of C4orf14 specifically affected components of the small subunit, leading to decreased protein synthesis in the organelle. The GTPase of C4orf14 was critical to its interaction with the 28S subunit, as was GTP. Therefore, we propose that C4orf14, with bound GTP, binds to components of the 28S subunit facilitating its assembly, and GTP hydrolysis acts as the release mechanism. C4orf14 was also found to be associated with human mitochondrial nucleoids, and C4orf14 gene silencing caused mitochondrial DNA depletion. In vitro C4orf14 is capable of binding to DNA. The association of C4orf14 with mitochondrial translation factors and the mitochondrial nucleoid suggests that the 28S subunit is assembled at the mitochondrial nucleoid, enabling the direct transfer of messenger RNA from the nucleoid to the ribosome in the organelle.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 7
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    Centromere Remodeling in Hoolock leuconedys (Hylobatidae) by a New Transposable Element Unique to the Gibbons (2012)
    Oxford University Press
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    Publication Date: 2012-07-11
    Description: Gibbons (Hylobatidae) shared a common ancestor with the other hominoids only 15–18 million years ago. Nevertheless, gibbons show very distinctive features that include heavily rearranged chromosomes. Previous observations indicate that this phenomenon may be linked to the attenuated epigenetic repression of transposable elements (TEs) in gibbon species. Here we describe the massive expansion of a repeat in almost all the centromeres of the eastern hoolock gibbon ( Hoolock leuconedys ). We discovered that this repeat is a new composite TE originating from the combination of portions of three other elements (L1ME5, Alu Sz6, and SVA_A) and thus named it LAVA. We determined that this repeat is found in all the gibbons but does not occur in other hominoids. Detailed investigation of 46 different LAVA elements revealed that the majority of them have target site duplications (TSDs) and a poly-A tail, suggesting that they have been retrotransposing in the gibbon genome. Although we did not find a direct correlation between the emergence of LAVA elements and human–gibbon synteny breakpoints, this new composite transposable element is another mark of the great plasticity of the gibbon genome. Moreover, the centromeric expansion of LAVA insertions in the hoolock closely resembles the massive centromeric expansion of the KERV-1 retroelement reported for wallaby (marsupial) interspecific hybrids. The similarity between the two phenomena is consistent with the hypothesis that evolution of the gibbons is characterized by defects in epigenetic repression of TEs, perhaps triggered by interspecific hybridization.
    Electronic ISSN: 1759-6653
    Topics: Biology
    Published by Oxford University Press
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  • 8
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    Phosphorylated (pT371)TRF1 is recruited to sites of DNA damage to facilitate homologous recombination and checkpoint activation (2013)
    Oxford University Press
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    Publication Date: 2013-12-07
    Description: TRF1, a duplex telomeric DNA-binding protein, plays an important role in telomere metabolism. We have previously reported that a fraction of endogenous TRF1 can stably exist free of telomere chromatin when it is phosphorylated at T371 by Cdk1; however, the role of this telomere-free (pT371)TRF1 has yet to be fully characterized. Here we show that phosphorylated (pT371)TRF1 is recruited to sites of DNA damage, forming damage-induced foci in response to ionizing radiation (IR), etoposide and camptothecin. We find that IR-induced (pT371)TRF1 foci formation is dependent on the ATM- and Mre11/Rad50/Nbs1-mediated DNA damage response. While loss of functional BRCA1 impairs the formation of IR-induced (pT371)TRF1 foci, depletion of either 53BP1 or Rif1 stimulates IR-induced (pT371)TRF1 foci formation. In addition, we show that TRF1 depletion or the lack of its phosphorylation at T371 impairs DNA end resection and repair of nontelomeric DNA double-strand breaks by homologous recombination. The lack of TRF1 phosphorylation at T371 also hampers the activation of the G2/M checkpoint and sensitizes cells to PARP inhibition, IR and camptothecin. Collectively, these results reveal a novel but important function of phosphorylated (pT371)TRF1 in facilitating DNA double-strand break repair and the maintenance of genome integrity.
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    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 9
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    The Drosophila Huntington's disease gene ortholog dhtt influences chromatin regulation during development (2014)
    Oxford University Press
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    Publication Date: 2014-12-24
    Description: Huntington's disease is an autosomal dominant neurodegenerative disorder caused by a CAG expansion mutation in HTT , the gene encoding huntingtin. Evidence from both human genotype–phenotype relationships and mouse model systems suggests that the mutation acts by dysregulating some normal activity of huntingtin. Recent work in the mouse has revealed a role for huntingtin in epigenetic regulation during development. Here, we examine the role of the Drosophila huntingtin ortholog ( dhtt ) in chromatin regulation in the development of the fly. Although null dhtt mutants display no overt phenotype, we found that dhtt acts as a suppressor of position-effect variegation (PEV), suggesting that it influences chromatin organization. We demonstrate that dhtt affects heterochromatin spreading in a PEV model by modulating histone H3K9 methylation levels at the heterochromatin–euchromatin boundary. To gain mechanistic insights into how dhtt influences chromatin function, we conducted a candidate genetic screen using RNAi lines targeting known PEV modifier genes. We found that dhtt modifies phenotypes caused by knockdown of a number of key epigenetic regulators, including chromatin-associated proteins, histone demethylases (HDMs) and methyltransferases. Notably, dhtt strongly modifies phenotypes resulting from loss of the HDM dLsd1 , in both the ovary and wing, and we demonstrate that dhtt appears to act as a facilitator of dLsd1 function in regulating global histone H3K4 methylation levels. These findings suggest that a fundamental aspect of huntingtin function in heterochromatin/euchromatin organization is evolutionarily conserved across phyla.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 10
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    Expression of SMARCB1 (INI1) mutations in familial schwannomatosis (2012)
    Oxford University Press
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    Publication Date: 2012-12-01
    Description: Genetic changes in the SMARCB1 tumor suppressor gene have recently been reported in tumors and blood from families with schwannomatosis. Exon scanning of all nine SMARCB1 exons in genomic DNA from our cohort of families meeting the criteria for ‘definite’ or ‘presumptive’ schwannomatosis previously revealed constitutional alterations in 13 of 19 families (68%). Screening of four new familial schwannomatosis probands identified one additional constitutional alteration. We confirmed the presence of mRNA transcripts for two missense alterations, four mutations of conserved splice motifs and two additional mutations, in less conserved sequences, which also affect splicing. Furthermore, we found that transcripts for a rare 3'-untranslated region (c.*82C 〉 T) alteration shared by four unrelated families did not produce splice variants but did show unequal allelic expression, suggesting that the alteration is either causative itself or linked to an unidentified causative mutation. Overexpression studies in cells lacking SMARCB1 suggest that mutant SMARCB1 proteins, like wild-type SMARCB1 protein, retain the ability to suppress cyclin D1 activity. These data, together with the expression of SMARCB1 protein in a proportion of cells from schwannomatosis-related schwannomas, suggest that these tumors develop through a mechanism that is distinct from that of rhabdoid tumors in which SMARCB1 protein is completely absent in tumor cells.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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