Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 37

Publication Record

Connections

A senataxin-associated exonuclease SAN1 is required for resistance to DNA interstrand cross-links.
Andrews AM, McCartney HJ, Errington TM, D'Andrea AD, Macara IG
(2018) Nat Commun 9: 2592
MeSH Terms: Animals, DNA Damage, DNA Helicases, DNA Repair, Enzyme Assays, Exodeoxyribonucleases, Fanconi Anemia Complementation Group D2 Protein, Female, Fibroblasts, Gene Knockdown Techniques, Gene Knockout Techniques, HEK293 Cells, HeLa Cells, Humans, Male, Mice, Mice, Knockout, RNA Helicases, RNA, Small Interfering, Recombinant Proteins, Signal Transduction, Trans-Activators
Show Abstract · Added August 17, 2020
Interstrand DNA cross-links (ICLs) block both replication and transcription, and are commonly repaired by the Fanconi anemia (FA) pathway. However, FA-independent repair mechanisms of ICLs remain poorly understood. Here we report a previously uncharacterized protein, SAN1, as a 5' exonuclease that acts independently of the FA pathway in response to ICLs. Deletion of SAN1 in HeLa cells and mouse embryonic fibroblasts causes sensitivity to ICLs, which is prevented by re-expression of wild type but not nuclease-dead SAN1. SAN1 deletion causes DNA damage and radial chromosome formation following treatment with Mitomycin C, phenocopying defects in the FA pathway. However, SAN1 deletion is not epistatic with FANCD2, a core FA pathway component. Unexpectedly, SAN1 binds to Senataxin (SETX), an RNA/DNA helicase that resolves R-loops. SAN1-SETX binding is increased by ICLs, and is required to prevent cross-link sensitivity. We propose that SAN1 functions with SETX in a pathway necessary for resistance to ICLs.
0 Communities
0 Members
0 Resources
MeSH Terms
Müller glial microRNAs are required for the maintenance of glial homeostasis and retinal architecture.
Wohl SG, Jorstad NL, Levine EM, Reh TA
(2017) Nat Commun 8: 1603
MeSH Terms: 3T3 Cells, Animals, Cell Movement, Cells, Cultured, DEAD-box RNA Helicases, Ependymoglial Cells, Gene Expression Profiling, Homeostasis, Mice, Mice, Knockout, Mice, Transgenic, MicroRNAs, Microscopy, Confocal, Neuroglia, Retina, Ribonuclease III
Show Abstract · Added February 14, 2018
To better understand the roles of microRNAs in glial function, we used a conditional deletion of Dicer1 (Dicer-CKO) in retinal Müller glia (MG). Dicer1 deletion from the MG leads to an abnormal migration of the cells as early as 1 month after the deletion. By 6 months after Dicer1 deletion, the MG form large aggregations and severely disrupt normal retinal architecture and function. The most highly upregulated gene in the Dicer-CKO MG is the proteoglycan Brevican (Bcan) and overexpression of Bcan results in similar aggregations of the MG in wild-type retina. One potential microRNA that regulates Bcan is miR-9, and overexpression of miR-9 can partly rescue the effects of Dicer1 deletion on the MG phenotype. We also find that MG from retinitis pigmentosa patients display an increase in Brevican immunoreactivity at sites of MG aggregation, linking the retinal remodeling that occurs in chronic disease with microRNAs.
0 Communities
1 Members
0 Resources
16 MeSH Terms
Nup42 and IP coordinate Gle1 stimulation of Dbp5/DDX19B for mRNA export in yeast and human cells.
Adams RL, Mason AC, Glass L, Aditi , Wente SR
(2017) Traffic 18: 776-790
MeSH Terms: Active Transport, Cell Nucleus, DEAD-box RNA Helicases, Humans, Nuclear Pore, Nuclear Pore Complex Proteins, Nucleocytoplasmic Transport Proteins, Phytic Acid, RNA, Messenger, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins
Show Abstract · Added March 30, 2018
The mRNA lifecycle is driven through spatiotemporal changes in the protein composition of mRNA particles (mRNPs) that are triggered by RNA-dependent DEAD-box protein (Dbp) ATPases. As mRNPs exit the nuclear pore complex (NPC) in Saccharomyces cerevisiae, this remodeling occurs through activation of Dbp5 by inositol hexakisphosphate (IP )-bound Gle1. At the NPC, Gle1 also binds Nup42, but Nup42's molecular function is unclear. Here we employ the power of structure-function analysis in S. cerevisiae and human (h) cells, and find that the high-affinity Nup42-Gle1 interaction is integral to Dbp5 (hDDX19B) activation and efficient mRNA export. The Nup42 carboxy-terminal domain (CTD) binds Gle1/hGle1B at an interface distinct from the Gle1-Dbp5/hDDX19B interaction site. A nup42-CTD/gle1-CTD/Dbp5 trimeric complex forms in the presence of IP . Deletion of NUP42 abrogates Gle1-Dbp5 interaction, and disruption of the Nup42 or IP binding interfaces on Gle1/hGle1B leads to defective mRNA export in S. cerevisiae and human cells. In vitro, Nup42-CTD and IP stimulate Gle1/hGle1B activation of Dbp5 and DDX19B recombinant proteins in similar, nonadditive manners, demonstrating complete functional conservation between humans and S. cerevisiae. Together, a highly conserved mechanism governs spatial coordination of mRNP remodeling during export. This has implications for understanding human disease mutations that perturb the Nup42-hGle1B interaction.
© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
0 Communities
1 Members
0 Resources
10 MeSH Terms
A role for Gle1, a regulator of DEAD-box RNA helicases, at centrosomes and basal bodies.
Jao LE, Akef A, Wente SR
(2017) Mol Biol Cell 28: 120-127
MeSH Terms: Active Transport, Cell Nucleus, Adenosine Triphosphatases, Antigens, Basal Bodies, Centrosome, DEAD-box RNA Helicases, Nuclear Pore, Nuclear Pore Complex Proteins, Nucleocytoplasmic Transport Proteins, Protein Binding, RNA Transport, RNA, Messenger, RNA-Binding Proteins, Zebrafish Proteins
Show Abstract · Added April 14, 2017
Control of organellar assembly and function is critical to eukaryotic homeostasis and survival. Gle1 is a highly conserved regulator of RNA-dependent DEAD-box ATPase proteins, with critical roles in both mRNA export and translation. In addition to its well-defined interaction with nuclear pore complexes, here we find that Gle1 is enriched at the centrosome and basal body. Gle1 assembles into the toroid-shaped pericentriolar material around the mother centriole. Reduced Gle1 levels are correlated with decreased pericentrin localization at the centrosome and microtubule organization defects. Of importance, these alterations in centrosome integrity do not result from loss of mRNA export. Examination of the Kupffer's vesicle in Gle1-depleted zebrafish revealed compromised ciliary beating and developmental defects. We propose that Gle1 assembly into the pericentriolar material positions the DEAD-box protein regulator to function in localized mRNA metabolism required for proper centrosome function.
© 2017 Jao et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
0 Communities
1 Members
0 Resources
14 MeSH Terms
Iron Toxicity in the Retina Requires Alu RNA and the NLRP3 Inflammasome.
Gelfand BD, Wright CB, Kim Y, Yasuma T, Yasuma R, Li S, Fowler BJ, Bastos-Carvalho A, Kerur N, Uittenbogaard A, Han YS, Lou D, Kleinman ME, McDonald WH, Núñez G, Georgel P, Dunaief JL, Ambati J
(2015) Cell Rep 11: 1686-93
MeSH Terms: Alu Elements, Animals, Carrier Proteins, Caspase 1, DEAD-box RNA Helicases, Inflammasomes, Iron, Mice, Mice, Inbred C57BL, NLR Family, Pyrin Domain-Containing 3 Protein, RNA-Binding Proteins, Retinal Pigment Epithelium, Ribonuclease III
Show Abstract · Added January 26, 2016
Excess iron induces tissue damage and is implicated in age-related macular degeneration (AMD). Iron toxicity is widely attributed to hydroxyl radical formation through Fenton's reaction. We report that excess iron, but not other Fenton catalytic metals, induces activation of the NLRP3 inflammasome, a pathway also implicated in AMD. Additionally, iron-induced degeneration of the retinal pigmented epithelium (RPE) is suppressed in mice lacking inflammasome components caspase-1/11 or Nlrp3 or by inhibition of caspase-1. Iron overload increases abundance of RNAs transcribed from short interspersed nuclear elements (SINEs): Alu RNAs and the rodent equivalent B1 and B2 RNAs, which are inflammasome agonists. Targeting Alu or B2 RNA prevents iron-induced inflammasome activation and RPE degeneration. Iron-induced SINE RNA accumulation is due to suppression of DICER1 via sequestration of the co-factor poly(C)-binding protein 2 (PCBP2). These findings reveal an unexpected mechanism of iron toxicity, with implications for AMD and neurodegenerative diseases associated with excess iron.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
13 MeSH Terms
Gonadotrope-specific deletion of Dicer results in severely suppressed gonadotropins and fertility defects.
Wang H, Graham I, Hastings R, Gunewardena S, Brinkmeier ML, Conn PM, Camper SA, Kumar TR
(2015) J Biol Chem 290: 2699-714
MeSH Terms: Animals, DEAD-box RNA Helicases, Female, Fertility, Gonadotrophs, Gonadotropins, Male, Mice, Mice, Knockout, MicroRNAs, Rats, Real-Time Polymerase Chain Reaction, Ribonuclease III
Show Abstract · Added February 19, 2015
Pituitary gonadotropins follicle-stimulating hormone and luteinizing hormone are heterodimeric glycoproteins expressed in gonadotropes. They act on gonads and promote their development and functions including steroidogenesis and gametogenesis. Although transcriptional regulation of gonadotropin subunits has been well studied, the post-transcriptional regulation of gonadotropin subunits is not well understood. To test if microRNAs regulate the hormone-specific gonadotropin β subunits in vivo, we deleted Dicer in gonadotropes by a Cre-lox genetic approach. We found that many of the DICER-dependent microRNAs, predicted in silico to bind gonadotropin β subunit mRNAs, were suppressed in purified gonadotropes of mutant mice. Loss of DICER-dependent microRNAs in gonadotropes resulted in profound suppression of gonadotropin-β subunit proteins and, consequently, the heterodimeric hormone secretion. In addition to suppression of basal levels, interestingly, the post-gonadectomy-induced rise in pituitary gonadotropin synthesis and secretion were both abolished in mutants, indicating a defective gonadal negative feedback control. Furthermore, mutants lacking Dicer in gonadotropes displayed severely reduced fertility and were rescued with exogenous hormones confirming that the fertility defects were secondary to suppressed gonadotropins. Our studies reveal that DICER-dependent microRNAs are essential for gonadotropin homeostasis and fertility in mice. Our studies also implicate microRNAs in gonadal feedback control of gonadotropin synthesis and secretion. Thus, DICER-dependent microRNAs confer a new layer of transcriptional and post-transcriptional regulation in gonadotropes to orchestrate the hypothalamus-pituitary-gonadal axis physiology.
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
0 Communities
1 Members
0 Resources
13 MeSH Terms
Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5'-diphosphates.
Goubau D, Schlee M, Deddouche S, Pruijssers AJ, Zillinger T, Goldeck M, Schuberth C, Van der Veen AG, Fujimura T, Rehwinkel J, Iskarpatyoti JA, Barchet W, Ludwig J, Dermody TS, Hartmann G, Reis e Sousa C
(2014) Nature 514: 372-375
MeSH Terms: Animals, Base Pairing, Base Sequence, DEAD Box Protein 58, DEAD-box RNA Helicases, Diphosphates, Female, Genome, Viral, Immunity, Innate, Male, Mice, RNA, Viral, Reoviridae
Show Abstract · Added January 21, 2015
Mammalian cells possess mechanisms to detect and defend themselves from invading viruses. In the cytosol, the RIG-I-like receptors (RLRs), RIG-I (retinoic acid-inducible gene I; encoded by DDX58) and MDA5 (melanoma differentiation-associated gene 5; encoded by IFIH1) sense atypical RNAs associated with virus infection. Detection triggers a signalling cascade via the adaptor MAVS that culminates in the production of type I interferons (IFN-α and β; hereafter IFN), which are key antiviral cytokines. RIG-I and MDA5 are activated by distinct viral RNA structures and much evidence indicates that RIG-I responds to RNAs bearing a triphosphate (ppp) moiety in conjunction with a blunt-ended, base-paired region at the 5'-end (reviewed in refs 1, 2, 3). Here we show that RIG-I also mediates antiviral responses to RNAs bearing 5'-diphosphates (5'pp). Genomes from mammalian reoviruses with 5'pp termini, 5'pp-RNA isolated from yeast L-A virus, and base-paired 5'pp-RNAs made by in vitro transcription or chemical synthesis, all bind to RIG-I and serve as RIG-I agonists. Furthermore, a RIG-I-dependent response to 5'pp-RNA is essential for controlling reovirus infection in cultured cells and in mice. Thus, the minimal determinant for RIG-I recognition is a base-paired RNA with 5'pp. Such RNAs are found in some viruses but not in uninfected cells, indicating that recognition of 5'pp-RNA, like that of 5'ppp-RNA, acts as a powerful means of self/non-self discrimination by the innate immune system.
0 Communities
1 Members
0 Resources
13 MeSH Terms
Nucleoporin FG domains facilitate mRNP remodeling at the cytoplasmic face of the nuclear pore complex.
Adams RL, Terry LJ, Wente SR
(2014) Genetics 197: 1213-24
MeSH Terms: Cloning, Molecular, Cytoplasm, DEAD-box RNA Helicases, Genetic Vectors, In Situ Hybridization, Fluorescence, Membrane Transport Proteins, Nuclear Pore Complex Proteins, Nuclear Proteins, Nucleocytoplasmic Transport Proteins, RNA, Messenger, RNA-Binding Proteins, Ribonucleoproteins, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins
Show Abstract · Added February 19, 2015
Directional export of messenger RNA (mRNA) protein particles (mRNPs) through nuclear pore complexes (NPCs) requires multiple factors. In Saccharomyces cerevisiae, the NPC proteins Nup159 and Nup42 are asymmetrically localized to the cytoplasmic face and have distinct functional domains: a phenylalanine-glycine (FG) repeat domain that docks mRNP transport receptors and domains that bind the DEAD-box ATPase Dbp5 and its activating cofactor Gle1, respectively. We speculated that the Nup42 and Nup159 FG domains play a role in positioning mRNPs for the terminal mRNP-remodeling steps carried out by Dbp5. Here we find that deletion (Δ) of both the Nup42 and Nup159 FG domains results in a cold-sensitive poly(A)+ mRNA export defect. The nup42ΔFG nup159ΔFG mutant also has synthetic lethal genetic interactions with dbp5 and gle1 mutants. RNA cross-linking experiments further indicate that the nup42ΔFG nup159ΔFG mutant has a reduced capacity for mRNP remodeling during export. To further analyze the role of these FG domains, we replaced the Nup159 or Nup42 FG domains with FG domains from other Nups. These FG "swaps" demonstrate that only certain FG domains are functional at the NPC cytoplasmic face. Strikingly, fusing the Nup42 FG domain to the carboxy-terminus of Gle1 bypasses the need for the endogenous Nup42 FG domain, highlighting the importance of proximal positioning for these factors. We conclude that the Nup42 and Nup159 FG domains target the mRNP to Gle1 and Dbp5 for mRNP remodeling at the NPC. Moreover, these results provide key evidence that character and context play a direct role in FG domain function and mRNA export.
Copyright © 2014 by the Genetics Society of America.
0 Communities
1 Members
0 Resources
14 MeSH Terms
Genome-wide study of percent emphysema on computed tomography in the general population. The Multi-Ethnic Study of Atherosclerosis Lung/SNP Health Association Resource Study.
Manichaikul A, Hoffman EA, Smolonska J, Gao W, Cho MH, Baumhauer H, Budoff M, Austin JH, Washko GR, Carr JJ, Kaufman JD, Pottinger T, Powell CA, Wijmenga C, Zanen P, Groen HJ, Postma DS, Wanner A, Rouhani FN, Brantly ML, Powell R, Smith BM, Rabinowitz D, Raffel LJ, Hinckley Stukovsky KD, Crapo JD, Beaty TH, Hokanson JE, Silverman EK, Dupuis J, O'Connor GT, Boezen HM, Rich SS, Barr RG
(2014) Am J Respir Crit Care Med 189: 408-18
MeSH Terms: Aged, Aged, 80 and over, Female, Follow-Up Studies, Genetic Markers, Genome-Wide Association Study, Genotyping Techniques, Humans, Male, Mannosidases, Middle Aged, N-Acetylglucosaminyltransferases, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Pulmonary Emphysema, RNA Helicases, Thiolester Hydrolases, Tomography, X-Ray Computed, United States, alpha-Mannosidase, snRNP Core Proteins
Show Abstract · Added February 15, 2014
RATIONALE - Pulmonary emphysema overlaps partially with spirometrically defined chronic obstructive pulmonary disease and is heritable, with moderately high familial clustering.
OBJECTIVES - To complete a genome-wide association study (GWAS) for the percentage of emphysema-like lung on computed tomography in the Multi-Ethnic Study of Atherosclerosis (MESA) Lung/SNP Health Association Resource (SHARe) Study, a large, population-based cohort in the United States.
METHODS - We determined percent emphysema and upper-lower lobe ratio in emphysema defined by lung regions less than -950 HU on cardiac scans. Genetic analyses were reported combined across four race/ethnic groups: non-Hispanic white (n = 2,587), African American (n = 2,510), Hispanic (n = 2,113), and Chinese (n = 704) and stratified by race and ethnicity.
MEASUREMENTS AND MAIN RESULTS - Among 7,914 participants, we identified regions at genome-wide significance for percent emphysema in or near SNRPF (rs7957346; P = 2.2 × 10(-8)) and PPT2 (rs10947233; P = 3.2 × 10(-8)), both of which replicated in an additional 6,023 individuals of European ancestry. Both single-nucleotide polymorphisms were previously implicated as genes influencing lung function, and analyses including lung function revealed independent associations for percent emphysema. Among Hispanics, we identified a genetic locus for upper-lower lobe ratio near the α-mannosidase-related gene MAN2B1 (rs10411619; P = 1.1 × 10(-9); minor allele frequency [MAF], 4.4%). Among Chinese, we identified single-nucleotide polymorphisms associated with upper-lower lobe ratio near DHX15 (rs7698250; P = 1.8 × 10(-10); MAF, 2.7%) and MGAT5B (rs7221059; P = 2.7 × 10(-8); MAF, 2.6%), which acts on α-linked mannose. Among African Americans, a locus near a third α-mannosidase-related gene, MAN1C1 (rs12130495; P = 9.9 × 10(-6); MAF, 13.3%) was associated with percent emphysema.
CONCLUSIONS - Our results suggest that some genes previously identified as influencing lung function are independently associated with emphysema rather than lung function, and that genes related to α-mannosidase may influence risk of emphysema.
0 Communities
1 Members
0 Resources
21 MeSH Terms
Conditional control of gene function by an invertible gene trap in zebrafish.
Ni TT, Lu J, Zhu M, Maddison LA, Boyd KL, Huskey L, Ju B, Hesselson D, Zhong TP, Page-McCaw PS, Stainier DY, Chen W
(2012) Proc Natl Acad Sci U S A 109: 15389-94
MeSH Terms: Alleles, Animals, DNA Nucleotidyltransferases, DNA Transposable Elements, Hepatocytes, Integrases, Liver, Mitochondria, Models, Genetic, Mutagenesis, Mutagens, Mutation, Phenotype, Polymerase Chain Reaction, RNA Helicases, Recombination, Genetic, Zebrafish
Show Abstract · Added January 7, 2014
Conditional mutations are essential for determining the stage- and tissue-specific functions of genes. Here we achieve conditional mutagenesis in zebrafish using FT1, a gene-trap cassette that can be stably inverted by both Cre and Flp recombinases. We demonstrate that intronic insertions in the gene-trapping orientation severely disrupt the expression of the host gene, whereas intronic insertions in the neutral orientation do not significantly affect host gene expression. Cre- and Flp-mediated recombination switches the orientation of the gene-trap cassette, permitting conditional rescue in one orientation and conditional knockout in the other. To illustrate the utility of this system we analyzed the functional consequence of intronic FT1 insertion in supv3l1, a gene encoding a mitochondrial RNA helicase. Global supv311 mutants have impaired mitochondrial function, embryonic lethality, and agenesis of the liver. Conditional rescue of supv311 expression in hepatocytes specifically corrected the liver defects. To test whether the liver function of supv311 is required for viability we used Flp-mediated recombination in the germline to generate a neutral allele at the locus. Subsequently, tissue-specific expression of Cre conditionally inactivated the targeted locus. Hepatocyte-specific inactivation of supv311 caused liver degeneration, growth retardation, and juvenile lethality, a phenotype that was less severe than the global disruption of supv311. Thus, supv311 is required in multiple tissues for organismal viability. Our mutagenesis approach is very efficient and could be used to generate conditional alleles throughout the zebrafish genome. Furthermore, because FT1 is based on the promiscuous Tol2 transposon, it should be applicable to many organisms.
1 Communities
3 Members
0 Resources
17 MeSH Terms