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https://www.readbyqxmd.com/read/28263325/genome-wide-mapping-of-long-range-contacts-unveils-clustering-of-dna-double-strand-breaks-at-damaged-active-genes
#1
François Aymard, Marion Aguirrebengoa, Emmanuelle Guillou, Biola M Javierre, Beatrix Bugler, Coline Arnould, Vincent Rocher, Jason S Iacovoni, Anna Biernacka, Magdalena Skrzypczak, Krzysztof Ginalski, Maga Rowicka, Peter Fraser, Gaëlle Legube
The ability of DNA double-strand breaks (DSBs) to cluster in mammalian cells has been a subject of intense debate in recent years. Here we used a high-throughput chromosome conformation capture assay (capture Hi-C) to investigate clustering of DSBs induced at defined loci in the human genome. The results unambiguously demonstrated that DSBs cluster, but only when they are induced within transcriptionally active genes. Clustering of damaged genes occurs primarily during the G1 cell-cycle phase and coincides with delayed repair...
March 6, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28242746/torsina-regulates-the-linc-to-moving-nuclei
#2
Daniel A Starr, Lesilee S Rose
How LINC complexes are regulated to connect nuclei to the cytoskeleton during nuclear migration is unknown. Saunders et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201507113) show that the AAA+ ATPase torsinA and its partner LAP1 are required for nuclear migration during fibroblast polarization by mediating the dynamics of LINC complexes.
March 6, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28178176/nlrp12-inflammasome-expression-in-the-rat-brain-in-response-to-lps-during-morphine-tolerance
#3
Sulie L Chang, Wenfei Huang, Xin Mao, Sabroni Sarkar
Morphine, an effective but addictive analgesic, can profoundly affect the inflammatory response to pathogens, and long-term use can result in morphine tolerance. Inflammasomes are protein complexes involved in the inflammatory response. The nucleotide-binding oligomerization domain-like receptor (NLR) Family Pyrin Domain Containing (NLRP) 12 (NLRP12) inflammasome has been reported to have anti-inflammatory activity. In this study, we examined the expression of NLRP12 inflammasome related genes in the adult F344 rat brain in response to the bacterial endotoxin lipopolysaccharide (LPS) in the presence and absence of morphine tolerance...
February 6, 2017: Brain Sciences
https://www.readbyqxmd.com/read/28134781/implications-for-diverse-functions-of-the-linc-complexes-based-on-the-structure
#4
REVIEW
Miki Hieda
The linker of nucleoskeleton and cytoskeleton (LINC) complex is composed of the outer and inner nuclear membrane protein families Klarsicht, Anc-1, and Syne homology (KASH), and Sad1 and UNC-84 (SUN) homology domain proteins. Increasing evidence has pointed to diverse functions of the LINC complex, such as in nuclear migration, nuclear integrity, chromosome movement and pairing during meiosis, and mechanotransduction to the genome. In metazoan cells, the nuclear envelope possesses the nuclear lamina, which is a thin meshwork of intermediate filaments known as A-type and B-type lamins and lamin binding proteins...
January 26, 2017: Cells
https://www.readbyqxmd.com/read/28102353/cofilin-regulates-nuclear-architecture-through-a-myosin-ii-dependent-mechanotransduction-module
#5
O'Neil Wiggan, Bryce Schroder, Diego Krapf, James R Bamburg, Jennifer G DeLuca
Structural features of the nucleus including shape, size and deformability impact its function affecting normal cellular processes such as cell differentiation and pathological conditions such as tumor cell migration. Despite the fact that abnormal nuclear morphology has long been a defining characteristic for diseases such as cancer relatively little is known about the mechanisms that control normal nuclear architecture. Mounting evidence suggests close coupling between F-actin cytoskeletal organization and nuclear morphology however, mechanisms regulating this coupling are lacking...
January 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28101692/the-assembly-and-function-of-perinuclear-actin-cap-in-migrating-cells
#6
Miloslava Maninova, Josef Caslavsky, Tomas Vomastek
Stress fibers are actin bundles encompassing actin filaments, actin-crosslinking, and actin-associated proteins that represent the major contractile system in the cell. Different types of stress fibers assemble in adherent cells, and they are central to diverse cellular processes including establishment of the cell shape, morphogenesis, cell polarization, and migration. Stress fibers display specific cellular organization and localization, with ventral fibers present at the basal side, and dorsal fibers and transverse actin arcs rising at the cell front from the ventral to the dorsal side and toward the nucleus...
January 18, 2017: Protoplasma
https://www.readbyqxmd.com/read/28091529/long-non-coding-rna-linc-ram-enhances-myogenic-differentiation-by-interacting-with-myod
#7
Xiaohua Yu, Yong Zhang, Tingting Li, Zhao Ma, Haixue Jia, Qian Chen, Yixia Zhao, Lili Zhai, Ran Zhong, Changyin Li, Xiaoting Zou, Jiao Meng, Antony K Chen, Pier Lorenzo Puri, Meihong Chen, Dahai Zhu
Long non-coding RNAs (lncRNAs) are important regulators of diverse biological processes. Here we report on functional identification and characterization of a novel long intergenic non-coding RNA with MyoD-regulated and skeletal muscle-restricted expression that promotes the activation of the myogenic program, and is therefore termed Linc-RAM (Linc-RNA Activator of Myogenesis). Linc-RAM is transcribed from an intergenic region of myogenic cells and its expression is upregulated during myogenesis. Notably, in vivo functional studies show that Linc-RAM knockout mice display impaired muscle regeneration due to the differentiation defect of satellite cells...
January 16, 2017: Nature Communications
https://www.readbyqxmd.com/read/28077629/sun2-silencing-impairs-cd4-t-cell-proliferation-and-alters-sensitivity-to-hiv-1-infection-independently-of-cyclophilin-a
#8
Daniel A Donahue, Françoise Porrot, Norbert Couespel, Olivier Schwartz
Linker of nucleoskeleton and cytoskeleton (LINC) complexes connect the nucleus to the cytoskeleton in eukaryotic cells. We previously reported that the overexpression of SUN2, an inner nuclear membrane protein and LINC complex component, inhibits HIV infection between the steps of reverse transcription and nuclear import in a capsid-specific manner. We also reported that SUN2 silencing does not modulate HIV infection in several cell lines. Silencing of SUN2 was recently reported to decrease HIV infection of CD4 T cells, an effect which was suggested to result from modulation of cyclophilin A (CypA)-dependent steps of HIV infection...
March 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28060557/control-of-nuclear-organization-by-f-actin-binding-proteins
#9
Karin Pfisterer, Asier Jayo, Maddy Parsons
The regulation of nuclear shape and deformability is a key factor in controlling diverse events from embryonic development to cancer cell metastasis, but the mechanisms governing this process are still unclear. Our recent study demonstrated an unexpected role for the F-actin bundling protein fascin in controlling nuclear plasticity through a direct interaction with Nesprin-2. Nesprin-2 is a component of the LINC complex that is known to couple the F-actin cytoskeleton to the nuclear envelope. We demonstrated that fascin, which is predominantly associated with peripheral F-actin rich filopodia, binds directly to Nesprin-2 at the nuclear envelope in a range of cell types...
January 6, 2017: Nucleus
https://www.readbyqxmd.com/read/28049722/the-linc-complex-contributes-to-heterochromatin-organisation-and-transcriptional-gene-silencing-in-plants
#10
Axel Poulet, Céline Duc, Maxime Voisin, Sophie Desset, Sylvie Tutois, Emmanuel Vanrobays, Matthias Benoit, David E Evans, Aline V Probst, Christophe Tatout
The LInker of Nucleoskeleton and Cytoskeleton (LINC) complex is an evolutionary well-conserved protein bridge connecting the cytoplasmic and nuclear compartments across the nuclear membrane. While recent data support its function in nuclear morphology and meiosis, its implication in chromatin organisation has not been studied in plants. Here 3D imaging methods have been used to investigate nuclear morphology and chromatin organisation in interphase nuclei of the model plant Arabidopsis thaliana, in which heterochromatin cluster in conspicuous chromatin domains called chromocentres...
January 3, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28035049/opposing-roles-for-distinct-linc-complexes-in-regulation-of-the-small-gtpase-rhoa
#11
Ketan Thakar, Christopher K May, Anna Rogers, Christopher W Carroll
Linker of Nucleoskeleton and Cytoskeleton (LINC) complexes span the nuclear envelope and transduce force from dynamic cytoskeletal networks to the nuclear lamina. Here we show that LINC complexes also signal from the nuclear envelope to critical regulators of the actin cytoskeleton. Specifically, we find that LINC complexes that contain the inner nuclear membrane protein Sun2 promote focal adhesion assembly by activating the small GTPase RhoA. A key effector in this process is the transcription factor/coactivator complex composed of SRF/Mkl1...
January 1, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/27979987/altered-nuclear-dynamics-in-mdx-myofibers
#12
Shama R Iyer, Sameer B Shah, Ana P Valencia, Martin F Schneider, Erick O Hernandez-Ochoa, Joseph P Stains, Silvia S Blemker, Richard M Lovering
Duchenne muscular dystrophy (DMD) is a genetic disorder in which the absence of dystrophin leads to progressive muscle degeneration and weakness. While the genetic basis is known, the pathophysiology of dystrophic skeletal muscle remains unclear. We examined nuclear movement in wild type (WT) and dystrophin-null (MDX) mouse myofibers. We also examined expression of proteins in the LINC (linkers of nucleoskeleton and cytoskeleton) complex as well as nuclear transcriptional activity via histone H3 acetylation and polyadenylate-binding nuclear protein-1...
December 15, 2016: Journal of Applied Physiology
https://www.readbyqxmd.com/read/27974481/unc-84-linc-ing-chromosome-movement-and-double-strand-break-repair
#13
Nicola Silva, Verena Jantsch
Assaults to our DNA take place at a high frequency and are incompatible with life. In this issue, Lawrence et al. (2016. J. Cell Biol https://doi.org/10.1083/jcb.201604112) demonstrate that a novel complex links the nucleus with cytoplasmic microtubules for the promotion of DNA repair by homologous recombination.
December 19, 2016: Journal of Cell Biology
https://www.readbyqxmd.com/read/27956467/linc-complexes-promote-homologous-recombination-in-part-through-inhibition-of-nonhomologous-end-joining
#14
Katherine S Lawrence, Erin C Tapley, Victor E Cruz, Qianyan Li, Kayla Aung, Kevin C Hart, Thomas U Schwartz, Daniel A Starr, JoAnne Engebrecht
The Caenorhabditis elegans SUN domain protein, UNC-84, functions in nuclear migration and anchorage in the soma. We discovered a novel role for UNC-84 in DNA damage repair and meiotic recombination. Loss of UNC-84 leads to defects in the loading and disassembly of the recombinase RAD-51. Similar to mutations in Fanconi anemia (FA) genes, unc-84 mutants and human cells depleted of Sun-1 are sensitive to DNA cross-linking agents, and sensitivity is rescued by the inactivation of nonhomologous end joining (NHEJ)...
December 19, 2016: Journal of Cell Biology
https://www.readbyqxmd.com/read/27905489/the-mammalian-linc-complex-regulates-genome-transcriptional-responses-to-substrate-rigidity
#15
Samer G Alam, Qiao Zhang, Nripesh Prasad, Yuan Li, Srikar Chamala, Ram Kuchibhotla, Birendra Kc, Varun Aggarwal, Shristi Shrestha, Angela L Jones, Shawn E Levy, Kyle J Roux, Jeffrey A Nickerson, Tanmay P Lele
Mechanical integration of the nucleus with the extracellular matrix (ECM) is established by linkage between the cytoskeleton and the nucleus. This integration is hypothesized to mediate sensing of ECM rigidity, but parsing the function of nucleus-cytoskeleton linkage from other mechanisms has remained a central challenge. Here we took advantage of the fact that the LINC (linker of nucleoskeleton and cytoskeleton) complex is a known molecular linker of the nucleus to the cytoskeleton, and asked how it regulates the sensitivity of genome-wide transcription to substratum rigidity...
December 1, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27889481/mitotic-nuclear-envelope-breakdown-and-spindle-nucleation-are-controlled-by-interphase-contacts-between-centromeres-and-the-nuclear-envelope
#16
Alfonso Fernández-Álvarez, Cécile Bez, Eileen T O'Toole, Mary Morphew, Julia Promisel Cooper
Faithful genome propagation requires coordination between nuclear envelope (NE) breakdown, spindle formation, and chromosomal events. The conserved linker of nucleoskeleton and cytoskeleton (LINC) complex connects fission yeast centromeres and the centrosome, across the NE, during interphase. During meiosis, LINC connects the centrosome with telomeres rather than centromeres. We previously showed that loss of telomere-LINC contacts compromises meiotic spindle formation. Here, we define the precise events regulated by telomere-LINC contacts and address the analogous possibility that centromeres regulate mitotic spindle formation...
December 5, 2016: Developmental Cell
https://www.readbyqxmd.com/read/27858498/sun1-splice-variants-sun1_888-sun1_785-and-predominant-sun1_916-variably-function-in-directional-cell-migration
#17
Yu Nishioka, Hiromasa Imaizumi, Junko Imada, Jun Katahira, Nariaki Matsuura, Miki Hieda
The LINC complex is a multifunctional protein complex that is involved in various processes at the nuclear envelope, such as nuclear migration, mechanotransduction and chromatin tethering in the meiotic phase. However, it remains unknown how these functions are regulated in different cell contexts. An inner nuclear membrane component of the LINC complex, SUN1, is ubiquitously expressed. The human SUN1 gene produces over 10 variants by alternative splicing. Although functions of SUN1 are relatively well characterized, functional differences among SUN1 splice variants are poorly characterized...
November 2016: Nucleus
https://www.readbyqxmd.com/read/27697922/nuclear-envelope-rupture-is-induced-by-actin-based-nucleus-confinement
#18
Emily M Hatch, Martin W Hetzer
Repeated rounds of nuclear envelope (NE) rupture and repair have been observed in laminopathy and cancer cells and result in intermittent loss of nucleus compartmentalization. Currently, the causes of NE rupture are unclear. Here, we show that NE rupture in cancer cells relies on the assembly of contractile actin bundles that interact with the nucleus via the linker of nucleoskeleton and cytoskeleton (LINC) complex. We found that the loss of actin bundles or the LINC complex did not rescue nuclear lamina defects, a previously identified determinant of nuclear membrane stability, but did decrease the number and size of chromatin hernias...
October 10, 2016: Journal of Cell Biology
https://www.readbyqxmd.com/read/27697906/nuclei-migrate-through-constricted-spaces-using-microtubule-motors-and-actin-networks-in-c-elegans-hypodermal-cells
#19
Courtney R Bone, Yu-Tai Chang, Natalie E Cain, Shaun P Murphy, Daniel A Starr
Cellular migrations through constricted spaces are a crucial aspect of many developmental and disease processes including hematopoiesis, inflammation and metastasis. A limiting factor in these events is nuclear deformation. Here, we establish an in vivo model in which nuclei can be visualized while moving through constrictions and use it to elucidate mechanisms for nuclear migration. C. elegans hypodermal P-cell larval nuclei traverse a narrow space that is about 5% their width. This constriction is blocked by fibrous organelles, structures that pass through P cells to connect the muscles to cuticle...
November 15, 2016: Development
https://www.readbyqxmd.com/read/27690270/hepatotoxicity-prediction-by-systems-biology-modeling-of-disturbed-metabolic-pathways-using-gene-expression-data
#20
Pablo Carbonell, Oriol Lopez, Alexander Amberg, Manuel Pastor, Ferran Sanz
The present study applies a systems biology approach for the in silico predictive modeling of drug toxicity on the basis of high-quality preclinical drug toxicity data with the aim of increasing the mechanistic understanding of toxic effects of compounds at different levels (pathway, cell, tissue, organ). The model development has been carried out using 77 compounds for which gene expression data are available in the LINCS database for primary human hepatocytes treated with the compounds, as well as rodent in vivo hepatotoxicity information is available in the eTOX database...
September 30, 2016: ALTEX
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