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https://www.readbyqxmd.com/read/29449800/robustness-and-vulnerability-of-the-autoregulatory-system-that-maintains-nuclear-tdp-43-levels-a-trade-off-hypothesis-for-als-pathology-based-on-in-silico-data
#1
Akihiro Sugai, Taisuke Kato, Akihide Koyama, Yuka Koike, Sou Kasahara, Takuya Konno, Tomohiko Ishihara, Osamu Onodera
Abnormal accumulation of TAR DNA-binding protein 43 (TDP-43) in the cytoplasm and its disappearance from the nucleus are pathological features of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) and are directly involved in the pathogenesis of these conditions. TDP-43 is an essential nuclear protein that readily aggregates in a concentration-dependent manner. Therefore, cells must strictly maintain an appropriate amount of nuclear TDP-43. In one relevant maintenance mechanism, TDP-43 binds to its pre-mRNA and promotes alternative splicing, resulting in mRNA degradation via nonsense-mediated mRNA decay...
2018: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/29444957/p38-activation-induces-the-dissociation-of-tristetraprolin-from-argonaute-2-to-increase-are-mrna-stabilization
#2
Mei-Yan Qi, Jing-Wen Song, Zhuo Zhang, Shuang Huang, Qing Jing
Tristetraprolin (TTP) destabilizes AU-rich element (ARE)-containing mRNA by directly binding with their 3'UTR. P38 stimulation substantially increases ARE-mRNA stability, at least through repressing TTP. However, the mechanism by which P38 keeps TTP inactive has not been fully understood. TTP and ARE-mRNA localize to processing bodies (PBs), the mRNA granules associated with mRNA silencing. Here, we detected the influence of P38 upon TTP localization within PBs and found that P38 regulates TTP localization within PBs...
February 14, 2018: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29431480/identification-of-a-novel-nonsense-aspm-mutation-in-a-large-consanguineous-pakistani-family-using-targeted-next-generation-sequencing
#3
Amjad Khan, Rongrong Wang, Shirui Han, Wasim Ahmad, Xue Zhang
AIMS: To identify the pathogenic mutation underlying microcephaly primary hereditary (MCPH) in a large consanguineous Pakistani family. METHODS: A five-generation family with an autosomal recessive transmission of MCPH was recruited. Targeted next-generation DNA sequencing was carried out to analyze the genomic DNA sample from the proband with MCPH using a previously designed panel targeting 46 known microcephaly-causing genes. Sanger sequencing was performed to verify all identified variants...
February 12, 2018: Genetic Testing and Molecular Biomarkers
https://www.readbyqxmd.com/read/29429924/the-tia1-rna-binding-protein-family-regulates-eif2ak2-mediated-stress-response-and-cell-cycle-progression
#4
Cindy Meyer, Aitor Garzia, Michael Mazzola, Stefanie Gerstberger, Henrik Molina, Thomas Tuschl
TIA1 and TIAL1 encode a family of U-rich element mRNA-binding proteins ubiquitously expressed and conserved in metazoans. Using PAR-CLIP, we determined that both proteins bind target sites with identical specificity in 3' UTRs and introns proximal to 5' as well as 3' splice sites. Double knockout (DKO) of TIA1 and TIAL1 increased target mRNA abundance proportional to the number of binding sites and also caused accumulation of aberrantly spliced mRNAs, most of which are subject to nonsense-mediated decay. Loss of PRKRA by mis-splicing triggered the activation of the double-stranded RNA (dsRNA)-activated protein kinase EIF2AK2/PKR and stress granule formation...
February 15, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29419787/biomarkers-responses-to-reductive-dechlorination-rates-and-oxygen-stress-in-bioaugmentation-culture-kb-1tm
#5
Gretchen L W Heavner, Cresten B Mansfeldt, Garrett E Debs, Sage T Hellerstedt, Annette R Rowe, Ruth E Richardson
Using mRNA transcript levels for key functional enzymes as proxies for the organohalide respiration (OHR) rate, is a promising approach for monitoring bioremediation populations in situ at chlorinated solvent-contaminated field sites. However, to date, no correlations have been empirically derived for chlorinated solvent respiring, Dehalococcoides mccartyi (DMC) containing, bioaugmentation cultures. In the current study, genome-wide transcriptome and proteome data were first used to confirm the most highly expressed OHR-related enzymes in the bioaugmentation culture, KB-1TM, including several reductive dehalogenases (RDases) and a Ni-Fe hydrogenase, Hup...
February 8, 2018: Microorganisms
https://www.readbyqxmd.com/read/29409120/tgf%C3%AE-activation-primes-canonical-wnt-signaling-through-the-downregulation-of-axin2
#6
Justin Gillespie, Rebecca L Ross, Clarissa Corinaldesi, Filomena Esteves, Emma Derrett-Smith, Michael F McDermott, Gina M Doody, Christopher P Denton, Paul Emery, Francesco Del Galdo
OBJECTIVES: Aberrant activation of Wnt signaling has been observed in systemic sclerosis (SSc) affected tissues. This study aimed to determine the role of transforming growth factor (TGF)β in driving the increased Wnt signaling, through modulation of AXIN2, a critical regulator of Wnt canonical pathway. METHODS: Canonical Wnt signaling activation was analyzed by TOPFlash TCF/LEF promoter assays. AXIN2 was evaluated in vitro by analysis of AXIN2 primary/mature transcripts expression and decay, TβRI blockade, siRNA-mediated TTP-1 depletion and through XAV-939-mediated AXIN2 stabilisation...
February 6, 2018: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/29408237/chromatin-modification-and-global-transcriptional-silencing-in-the-oocyte-mediated-by-the-mrna-decay-activator-zfp36l2
#7
Jennifer N Dumdie, Kyucheol Cho, Madhuvanthi Ramaiah, David Skarbrevik, Sergio Mora-Castilla, Deborah J Stumpo, Jens Lykke-Andersen, Louise C Laurent, Perry J Blackshear, Miles F Wilkinson, Heidi Cook-Andersen
Global transcriptional silencing is a highly conserved mechanism central to the oocyte-to-embryo transition. We report the unexpected discovery that global transcriptional silencing in oocytes depends on an mRNA decay activator. Oocyte-specific loss of ZFP36L2 an RNA-binding protein that promotes AU-rich element-dependent mRNA decay prevents global transcriptional silencing and causes oocyte maturation and fertilization defects, as well as complete female infertility in the mouse. Single-cell RNA sequencing revealed that ZFP36L2 downregulates mRNAs encoding transcription and chromatin modification regulators, including a large group of mRNAs for histone demethylases targeting H3K4 and H3K9, which we show are bound and degraded by ZFP36L2...
February 5, 2018: Developmental Cell
https://www.readbyqxmd.com/read/29397575/genotype-phenotype-investigation-of-35-patients-from-11-unrelated-families-with-camptodactyly-arthropathy-coxa-vara-pericarditis-cacp-syndrome
#8
Saliha Yilmaz, Dilek Uludağ Alkaya, Özgür Kasapçopur, Kenan Barut, Ekin S Akdemir, Cemre Celen, Mark W Youngblood, Katsuhito Yasuno, Kaya Bilguvar, Murat Günel, Beyhan Tüysüz
BACKGROUND: The camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) is a rare autosomal recessive condition characterized by camptodactyly, noninflammatory arthropathy, coxa vara, and pericarditis. CACP is caused by mutations in the proteoglycan 4 (PRG4) gene, which encodes a lubricating glycoprotein present in the synovial fluid and at the surface of articular cartilage. METHODS: In the present study, we compared the clinical and molecular findings of CACP syndrome in 35 patients from 11 unrelated families...
February 4, 2018: Molecular Genetics & Genomic Medicine
https://www.readbyqxmd.com/read/29396419/partial-androgen-insensitivity-syndrome-caused-by-a-deep-intronic-mutation-creating-an-alternative-splice-acceptor-site-of-the-ar-gene
#9
Hiroyuki Ono, Hirotomo Saitsu, Reiko Horikawa, Shinichi Nakashima, Yumiko Ohkubo, Kumiko Yanagi, Kazuhiko Nakabayashi, Maki Fukami, Yasuko Fujisawa, Tsutomu Ogata
Although partial androgen insensitivity syndrome (PAIS) is caused by attenuated responsiveness to androgens, androgen receptor gene (AR) mutations on the coding regions and their splice sites have been identified only in <25% of patients with a diagnosis of PAIS. We performed extensive molecular studies including whole exome sequencing in a Japanese family with PAIS, identifying a deep intronic variant beyond the branch site at intron 6 of AR (NM_000044.4:c.2450-42 G > A). This variant created the splice acceptor motif that was accompanied by pyrimidine-rich sequence and two candidate branch sites...
February 2, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29387902/lnc-ing-non-coding-rnas-with-metabolism-and-diabetes-roles-of-lncrnas
#10
REVIEW
Neha Goyal, Devesh Kesharwani, Malabika Datta
Type 2 diabetes is a complex metabolic disorder characterized by insulin resistance and pancreatic β-cell dysfunction. Deregulated glucose and lipid metabolism are the primary underlying manifestations associated with this disease and its complications. Long non-coding RNAs (lncRNAs) are a novel class of functional RNAs that regulate a variety of biological processes by a diverse interplay of mechanisms including recruitment of epigenetic modifiers, transcriptional and post-transcriptional regulation, control of mRNA decay, and sequestration of transcription factors...
January 31, 2018: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/29386391/arabidopsis-mrna-decay-landscape-arises-from-specialized-rna-decay-substrates-decapping-mediated-feedback-and-redundancy
#11
Reed S Sorenson, Malia J Deshotel, Katrina Johnson, Frederick R Adler, Leslie E Sieburth
The decay of mRNA plays a vital role in modulating mRNA abundance, which, in turn, influences cellular and organismal processes. In plants and metazoans, three distinct pathways carry out the decay of most cytoplasmic mRNAs: The mRNA decapping complex, which requires the scaffold protein VARICOSE (VCS), removes a protective 5' cap, allowing for 5' to 3' decay via EXORIBONUCLEASE4 (XRN4, XRN1 in metazoans and yeast), and both the exosome and SUPPRESSOR OF VCS (SOV)/DIS3L2 degrade RNAs in the 3' to 5' direction...
January 31, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29385657/in-silico-analysis-of-structural-modifications-in-and-around-the-integrin-%C3%AE-iib-genu-caused-by-itga2b-variants-in-human-platelets-with-emphasis-on-glanzmann-thrombasthenia
#12
Xavier Pillois, Pierre Peters, Karin Segers, Alan T Nurden
BACKGROUND: Studies on the inherited bleeding disorder, Glanzmann thrombasthenia (GT), have helped define the role of the αIIbβ3 integrin in platelet aggregation. Stable bent αIIbβ3 undergoes conformation changes on activation allowing fibrinogen binding and its taking an extended form. The αIIb genu assures the fulcrum of the bent state. Our goal was to determine how structural changes induced by missense mutations in the αIIb genu define GT phenotype. METHODS: Sanger sequencing of ITGA2B and ITGB3 in the index case followed by in silico modeling of all known GT-causing missense mutations extending from the lower part of the β-propeller, and through the thigh and upper calf-1 domains...
January 31, 2018: Molecular Genetics & Genomic Medicine
https://www.readbyqxmd.com/read/29382845/htlv-1-tax-plugs-and-freezes-upf1-helicase-leading-to-nonsense-mediated-mrna-decay-inhibition
#13
Francesca Fiorini, Jean-Philippe Robin, Joanne Kanaan, Malgorzata Borowiak, Vincent Croquette, Hervé Le Hir, Pierre Jalinot, Vincent Mocquet
Up-Frameshift Suppressor 1 Homolog (UPF1) is a key factor for nonsense-mediated mRNA decay (NMD), a cellular process that can actively degrade mRNAs. Here, we study NMD inhibition during infection by human T-cell lymphotropic virus type I (HTLV-1) and characterise the influence of the retroviral Tax factor on UPF1 activity. Tax interacts with the central helicase core domain of UPF1 and might plug the RNA channel of UPF1, reducing its affinity for nucleic acids. Furthermore, using a single-molecule approach, we show that the sequential interaction of Tax with a RNA-bound UPF1 freezes UPF1: this latter is less sensitive to the presence of ATP and shows translocation defects, highlighting the importance of this feature for NMD...
January 30, 2018: Nature Communications
https://www.readbyqxmd.com/read/29381060/p-bodies-composition-properties-and-functions
#14
Yang Luo, Zhenkun Na, Sarah A Slavoff
Processing bodies (P-bodies) are cytoplasmic ribonucleoprotein (RNP) granules primarily composed of translationally repressed mRNAs and proteins related to mRNA decay, suggesting roles in post-transcriptional regulation. P-bodies are conserved in eukaryotic cells and exhibit properties of liquid droplets. However, the function of P-bodies in translational repression and/or mRNA decay remains contentious. Here we review recent advances in our understanding of the molecular composition of P-bodies, the interactions and processes that regulate P-body liquid-liquid phase separation (LLPS), and the cellular localization of mRNA decay machinery, in the context of how these discoveries refine models of P-body function...
January 30, 2018: Biochemistry
https://www.readbyqxmd.com/read/29378013/a-conserved-structural-element-in-the-rna-helicase-upf1-regulates-its-catalytic-activity-in-an-isoform-specific-manner
#15
Manjeera Gowravaram, Fabien Bonneau, Joanne Kanaan, Vincent D Maciej, Francesca Fiorini, Saurabh Raj, Vincent Croquette, Hervé Le Hir, Sutapa Chakrabarti
The RNA helicase UPF1 is a key component of the nonsense mediated mRNA decay (NMD) pathway. Previous X-ray crystal structures of UPF1 elucidated the molecular mechanisms of its catalytic activity and regulation. In this study, we examine features of the UPF1 core and identify a structural element that adopts different conformations in the various nucleotide- and RNA-bound states of UPF1. We demonstrate, using biochemical and single molecule assays, that this structural element modulates UPF1 catalytic activity and thereby refer to it as the regulatory loop...
January 25, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29374277/cxorf56-a-dendritic-neuronal-protein-identified-as-a-new-candidate-gene-for-x-linked-intellectual-disability
#16
Annemieke J M H Verkerk, Shimriet Zeidler, Guido Breedveld, Lydia Overbeek, Daphne Huigh, Linda Koster, Herma van der Linde, Celine de Esch, Lies-Anne Severijnen, Bert B A de Vries, Sigrid M A Swagemakers, Rob Willemsen, A Jeannette M Hoogeboom, Peter J van der Spek, Ben A Oostra
Intellectual disability (ID) comprises a large group of heterogeneous disorders, often without a known molecular cause. X-linked ID accounts for 5-10% of male ID cases. We investigated a large, three-generation family with mild ID and behavior problems in five males and one female, with a segregation suggestive for X-linked inheritance. Linkage analysis mapped a disease locus to a 7.6 Mb candidate region on the X-chromosome (LOD score 3.3). Whole-genome sequencing identified a 2 bp insertion in exon 2 of the chromosome X open reading frame 56 gene (CXorf56), resulting in a premature stop codon...
January 26, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29374155/kruppel-like-factor-4-dependent-staufen1-mediated-mrna-decay-regulates-cortical-neurogenesis
#17
Byoung-San Moon, Jinlun Bai, Mingyang Cai, Chunming Liu, Jiandang Shi, Wange Lu
Kruppel-like factor 4 (Klf4) is a zinc-finger-containing protein that plays a critical role in diverse cellular physiology. While most of these functions attribute to its role as a transcription factor, it is postulated that Klf4 may play a role other than transcriptional regulation. Here we demonstrate that Klf4 loss in neural progenitor cells (NPCs) leads to increased neurogenesis and reduced self-renewal in mice. In addition, Klf4 interacts with RNA-binding protein Staufen1 (Stau1) and RNA helicase Ddx5/17...
January 26, 2018: Nature Communications
https://www.readbyqxmd.com/read/29374143/n6-methyladenosine-links-rna-metabolism-to-cancer-progression
#18
REVIEW
Dongjun Dai, Hanying Wang, Liyuan Zhu, Hongchuan Jin, Xian Wang
N6-methyladenosine (m6A) is the most abundant mRNA modification. With the development of antibody-based sequencing technologies and the findings of m6A-related "writers", "erasers", and "readers", the relationships between m6A and mRNA metabolism are emerging. The m6A modification influences almost every step of RNA metabolism that comprises mRNA processing, mRNA exporting from nucleus to cytoplasm, mRNA translation, mRNA decay, and the biogenesis of long-non-coding RNA (lncRNA) and microRNA (miRNA). Recently, more and more studies have found m6A is associated with cancer, contributing to the self-renewal of cancer stem cell, promotion of cancer cell proliferation, and resistance to radiotherapy or chemotherapy...
January 26, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29369522/uncovering-cell-type-specific-complexities-of-gene-expression-and-rna-metabolism-by-tu-tagging-and-ec-tagging
#19
REVIEW
Michael D Cleary
Cell type-specific transcription is a key determinant of cell fate and function. An ongoing challenge in biology is to develop robust and stringent biochemical methods to explore gene expression with cell type specificity. This challenge has become even greater as researchers attempt to apply high-throughput RNA analysis methods under in vivo conditions. TU-tagging and EC-tagging are in vivo biosynthetic RNA tagging techniques that allow spatial and temporal specificity in RNA purification. Spatial specificity is achieved through targeted expression of pyrimidine salvage enzymes (uracil phosphoribosyltransferase and cytosine deaminase) and temporal specificity is achieved by controlling exposure to bioorthogonal substrates of these enzymes (4-thiouracil and 5-ethynylcytosine)...
January 25, 2018: Wiley Interdisciplinary Reviews. Developmental Biology
https://www.readbyqxmd.com/read/29364236/determining-genome-wide-transcript-decay-rates-in-proliferating-and-quiescent-human-fibroblasts
#20
Mithun Mitra, Ha Neul Lee, Hilary A Coller
Quiescence is a temporary, reversible state in which cells have ceased cell division, but retain the capacity to proliferate. Multiple studies, including ours, have demonstrated that quiescence is associated with widespread changes in gene expression. Some of these changes occur through changes in the level or activity of proliferation-associated transcription factors, such as E2F and MYC. We have demonstrated that mRNA decay can also contribute to changes in gene expression between proliferating and quiescent cells...
January 2, 2018: Journal of Visualized Experiments: JoVE
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