COMMD1 Is Linked to the WASH Complex and Regulates Endosomal Trafficking of the Copper Transporter ATP7A
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Genetic Analysis of Retinopathy in Type 1 Diabetes
Genetic Analysis of Retinopathy in Type 1 Diabetes by Sayed Mohsen Hosseini A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Institute of Medical Science University of Toronto © Copyright by S. Mohsen Hosseini 2014 Genetic Analysis of Retinopathy in Type 1 Diabetes Sayed Mohsen Hosseini Doctor of Philosophy Institute of Medical Science University of Toronto 2014 Abstract Diabetic retinopathy (DR) is a leading cause of blindness worldwide. Several lines of evidence suggest a genetic contribution to the risk of DR; however, no genetic variant has shown convincing association with DR in genome-wide association studies (GWAS). To identify common polymorphisms associated with DR, meta-GWAS were performed in three type 1 diabetes cohorts of White subjects: Diabetes Complications and Control Trial (DCCT, n=1304), Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR, n=603) and Renin-Angiotensin System Study (RASS, n=239). Severe (SDR) and mild (MDR) retinopathy outcomes were defined based on repeated fundus photographs in each study graded for retinopathy severity on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. Multivariable models accounted for glycemia (measured by A1C), diabetes duration and other relevant covariates in the association analyses of additive genotypes with SDR and MDR. Fixed-effects meta- analysis was used to combine the results of GWAS performed separately in WESDR, ii RASS and subgroups of DCCT, defined by cohort and treatment group. Top association signals were prioritized for replication, based on previous supporting knowledge from the literature, followed by replication in three independent white T1D studies: Genesis-GeneDiab (n=502), Steno (n=936) and FinnDiane (n=2194). -
Epigenome-Wide Exploratory Study of Monozygotic Twins Suggests Differentially Methylated Regions to Associate with Hand Grip Strength
Biogerontology (2019) 20:627–647 https://doi.org/10.1007/s10522-019-09818-1 (0123456789().,-volV)( 0123456789().,-volV) RESEARCH ARTICLE Epigenome-wide exploratory study of monozygotic twins suggests differentially methylated regions to associate with hand grip strength Mette Soerensen . Weilong Li . Birgit Debrabant . Marianne Nygaard . Jonas Mengel-From . Morten Frost . Kaare Christensen . Lene Christiansen . Qihua Tan Received: 15 April 2019 / Accepted: 24 June 2019 / Published online: 28 June 2019 Ó The Author(s) 2019 Abstract Hand grip strength is a measure of mus- significant CpG sites or pathways were found, how- cular strength and is used to study age-related loss of ever two of the suggestive top CpG sites were mapped physical capacity. In order to explore the biological to the COL6A1 and CACNA1B genes, known to be mechanisms that influence hand grip strength varia- related to muscular dysfunction. By investigating tion, an epigenome-wide association study (EWAS) of genomic regions using the comb-p algorithm, several hand grip strength in 672 middle-aged and elderly differentially methylated regions in regulatory monozygotic twins (age 55–90 years) was performed, domains were identified as significantly associated to using both individual and twin pair level analyses, the hand grip strength, and pathway analyses of these latter controlling the influence of genetic variation. regions revealed significant pathways related to the Moreover, as measurements of hand grip strength immune system, autoimmune disorders, including performed over 8 years were available in the elderly diabetes type 1 and viral myocarditis, as well as twins (age 73–90 at intake), a longitudinal EWAS was negative regulation of cell differentiation. -
Centre for Arab Genomic Studies a Division of Sheikh Hamdan Award for Medical Sciences
Centre for Arab Genomic Studies A Division of Sheikh Hamdan Award for Medical Sciences The atalogue for ransmission enetics in rabs C T G A CTGA Database KIAA0196 Gene Alternative Names (Dandy-Walker malformation and cerebellar vermis KIAA0196 hypoplasia), congenital heart deformities (septal defects and aortic stenosis) and craniofacial Record Category dysmorphia (prominent occiput and forehead, low- Gene locus set ears, down-slanting palpebral fissures, depressed nasal bridge and micrognathia). WHO-ICD N/A to gene loci Molecular Genetics The KIAA0196 gene, located on the long arm of Incidence per 100,000 Live Births chromosome 8, spans a length of 67 kb. Its coding N/A to gene loci sequence consists of 31 exons and it encodes a 134 kDa protein product made up of 1159 amino acids. OMIM Number While the gene is ubiquitously expressed in the 610657 human body, it is found to be overexpressed in skeletal muscles. Heterozygous missense mutations Mode of Inheritance in the KIAA0196 gene are associated with Spastic N/A to gene loci Paraplegia 8, the most common being Val626Phe caused by a 1956G-T transversion; while a Gene Map Locus homozygous splice site mutation in the gene has 8q24.13 been linked to Ritscher-Schinzel Syndrome 1. Description Epidemiology in the Arab World The KIAA0196 gene encodes the strumpellin Saudi Arabia protein. The protein, found in the cytosol and Anazi et al. (2016) carried out a study to determine endoplasmic reticulum, forms a part of the WASH the diagnostic yield of genetic analysis tools core complex along with F-actin-capping protein compared to standard clinical evaluations. -
Supplemental Information
Supplemental information Dissection of the genomic structure of the miR-183/96/182 gene. Previously, we showed that the miR-183/96/182 cluster is an intergenic miRNA cluster, located in a ~60-kb interval between the genes encoding nuclear respiratory factor-1 (Nrf1) and ubiquitin-conjugating enzyme E2H (Ube2h) on mouse chr6qA3.3 (1). To start to uncover the genomic structure of the miR- 183/96/182 gene, we first studied genomic features around miR-183/96/182 in the UCSC genome browser (http://genome.UCSC.edu/), and identified two CpG islands 3.4-6.5 kb 5’ of pre-miR-183, the most 5’ miRNA of the cluster (Fig. 1A; Fig. S1 and Seq. S1). A cDNA clone, AK044220, located at 3.2-4.6 kb 5’ to pre-miR-183, encompasses the second CpG island (Fig. 1A; Fig. S1). We hypothesized that this cDNA clone was derived from 5’ exon(s) of the primary transcript of the miR-183/96/182 gene, as CpG islands are often associated with promoters (2). Supporting this hypothesis, multiple expressed sequences detected by gene-trap clones, including clone D016D06 (3, 4), were co-localized with the cDNA clone AK044220 (Fig. 1A; Fig. S1). Clone D016D06, deposited by the German GeneTrap Consortium (GGTC) (http://tikus.gsf.de) (3, 4), was derived from insertion of a retroviral construct, rFlpROSAβgeo in 129S2 ES cells (Fig. 1A and C). The rFlpROSAβgeo construct carries a promoterless reporter gene, the β−geo cassette - an in-frame fusion of the β-galactosidase and neomycin resistance (Neor) gene (5), with a splicing acceptor (SA) immediately upstream, and a polyA signal downstream of the β−geo cassette (Fig. -
Genome-Wide Screen Identifies Genes Whose Inactivation Confer Resistance to Cisplatin in Saccharomyces Cerevisiae
Research Article Genome-Wide Screen Identifies Genes Whose Inactivation Confer Resistance to Cisplatin in Saccharomyces cerevisiae Ruea-Yea Huang, Martha Eddy, Marija Vujcic, and David Kowalski Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York Abstract therapy (1). This may be due to the genomic instability of tumors, To identify novel genes that mediate cellular resistance to which gives rise to mutations or defects in multiple molecular cisplatin, we have screened the collection of Saccharomyces pathways. Both gain-of-function and loss-of-function mutations cerevisiae deletion strains. We have found reproducibly 22 can confer resistance to platinum compounds. The best known genes/open reading frames (ORF), which when deleted, confer examples are the loss of DNA mismatch repair (MMR) genes, resistance to cisplatin at a concentration that is lethal to wild- hMLH1, hMSH2, or hPMS2 (1, 4). MMR proteins function in type cells. Complementation of individual deletion strains recognition of damaged DNA adducts. Previous studies indicate with the corresponding wild-type gene abolished cisplatin that mutation or methylation-mediated silencing of these genes resistance, confirming that specific gene deletions caused the results in failure to recognize the adduct and propagate a signal to resistance. Twenty of the genes/ORFs identified have not been the apoptotic machinery, thereby producing low-level resistance to previously linked to cisplatin resistance and belong to several cisplatin (5). In addition, cisplatin treatment can enrich for malignant populations of cells that have lost DNA mismatch distinct functional groups. Major functional groups encode proteins involved in nucleotide metabolism, mRNA catabo- repair both in vitro and in vivo (4). -
Stranded DNA and Sensitizes Human Kidney Renal Clear Cell Carcinoma
RESEARCH ARTICLE Exosome component 1 cleaves single- stranded DNA and sensitizes human kidney renal clear cell carcinoma cells to poly(ADP-ribose) polymerase inhibitor Qiaoling Liu1†, Qi Xiao1†, Zhen Sun1†, Bo Wang2†, Lina Wang1, Na Wang1, Kai Wang1, Chengli Song1*, Qingkai Yang1* 1Institute of Cancer Stem Cell, DaLian Medical University, Dalian, China; 2Department of General Surgery, Second Affiliated Hospital, DaLian Medical University, Dalian, China Abstract Targeting DNA repair pathway offers an important therapeutic strategy for Homo sapiens (human) cancers. However, the failure of DNA repair inhibitors to markedly benefit patients necessitates the development of new strategies. Here, we show that exosome component 1 (EXOSC1) promotes DNA damages and sensitizes human kidney renal clear cell carcinoma (KIRC) cells to DNA repair inhibitor. Considering that endogenous source of mutation (ESM) constantly assaults genomic DNA and likely sensitizes human cancer cells to the inhibitor, we first analyzed the statistical relationship between the expression of individual genes and the mutations for KIRC. Among the candidates, EXOSC1 most notably promoted DNA damages and subsequent mutations via preferentially cleaving C site(s) in single-stranded DNA. Consistently, EXOSC1 was more *For correspondence: significantly correlated with C>A transversions in coding strands than these in template strands in [email protected] human KIRC. Notably, KIRC patients with high EXOSC1 showed a poor prognosis, and EXOSC1 (CS); sensitized human cancer cells to poly(ADP-ribose) polymerase inhibitors. These results show that [email protected] (QY) EXOSC1 acts as an ESM in KIRC, and targeting EXOSC1 might be a potential therapeutic strategy. †These authors contributed equally to this work Competing interests: The Introduction authors declare that no DNA damages and subsequent mutations are central to development, progression, and treatment competing interests exist. -
Aneuploidy: Using Genetic Instability to Preserve a Haploid Genome?
Health Science Campus FINAL APPROVAL OF DISSERTATION Doctor of Philosophy in Biomedical Science (Cancer Biology) Aneuploidy: Using genetic instability to preserve a haploid genome? Submitted by: Ramona Ramdath In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Science Examination Committee Signature/Date Major Advisor: David Allison, M.D., Ph.D. Academic James Trempe, Ph.D. Advisory Committee: David Giovanucci, Ph.D. Randall Ruch, Ph.D. Ronald Mellgren, Ph.D. Senior Associate Dean College of Graduate Studies Michael S. Bisesi, Ph.D. Date of Defense: April 10, 2009 Aneuploidy: Using genetic instability to preserve a haploid genome? Ramona Ramdath University of Toledo, Health Science Campus 2009 Dedication I dedicate this dissertation to my grandfather who died of lung cancer two years ago, but who always instilled in us the value and importance of education. And to my mom and sister, both of whom have been pillars of support and stimulating conversations. To my sister, Rehanna, especially- I hope this inspires you to achieve all that you want to in life, academically and otherwise. ii Acknowledgements As we go through these academic journeys, there are so many along the way that make an impact not only on our work, but on our lives as well, and I would like to say a heartfelt thank you to all of those people: My Committee members- Dr. James Trempe, Dr. David Giovanucchi, Dr. Ronald Mellgren and Dr. Randall Ruch for their guidance, suggestions, support and confidence in me. My major advisor- Dr. David Allison, for his constructive criticism and positive reinforcement. -
Molecular Mechanism for the Subversion of the Retromer Coat By
Molecular mechanism for the subversion of the PNAS PLUS retromer coat by the Legionella effector RidL Miguel Romano-Morenoa, Adriana L. Rojasa, Chad D. Williamsonb, David C. Gershlickb, María Lucasa, Michail N. Isupovc, Juan S. Bonifacinob, Matthias P. Machnerd,1, and Aitor Hierroa,e,1 aStructural Biology Unit, Centro de Investigación Cooperativa en Biociencias, 48160 Derio, Spain; bCell Biology and Neurobiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; cThe Henry Wellcome Building for Biocatalysis, Biosciences, University of Exeter, Exeter EX4 4SB, United Kingdom; dDivision of Molecular and Cellular Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; and eIKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain Edited by Ralph R. Isberg, Howard Hughes Medical Institute and Tufts University School of Medicine, Boston, MA, and approved November 13, 2017 (received for review August 30, 2017) Microbial pathogens employ sophisticated virulence strategies to VAMP7 together with several Rab GTPases that function along cause infections in humans. The intracellular pathogen Legionella distinct trafficking pathways (18), and the Tre-2/Bub2/Cdc16 pneumophila encodes RidL to hijack the host scaffold protein domain family member 5 (TBC1D5), a GTPase-activating pro- VPS29, a component of retromer and retriever complexes critical for tein (GAP) that causes Rab7 inactivation and redistribution to endosomal cargo recycling. Here, we determined the crystal structure the cytosol (14). of L. pneumophila RidL in complex with the human VPS29–VPS35 Recent biochemical and structural characterization of single retromer subcomplex. A hairpin loop protruding from RidL inserts subunits and subcomplexes from retromer have provided insights into a conserved pocket on VPS29 that is also used by cellular ligands, into its modular architecture and mechanisms of action. -
Structural Insights Into the Architecture and Membrane Interactions of the Conserved COMMD Proteins
RESEARCH ARTICLE Structural insights into the architecture and membrane interactions of the conserved COMMD proteins Michael D Healy1, Manuela K Hospenthal2†, Ryan J Hall1, Mintu Chandra1, Molly Chilton3, Vikas Tillu1, Kai-En Chen1, Dion J Celligoi2, Fiona J McDonald4, Peter J Cullen3, J Shaun Lott2, Brett M Collins1*, Rajesh Ghai1* 1Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Australia; 2School of Biological Sciences, The University of Auckland, Auckland, New Zealand; 3School of Biochemistry, Biomedical Sciences Building, University of Bristol, Bristol, United Kingdom; 4Department of Physiology, University of Otago, Dunedin, New Zealand Abstract The COMMD proteins are a conserved family of proteins with central roles in intracellular membrane trafficking and transcription. They form oligomeric complexes with each other and act as components of a larger assembly called the CCC complex, which is localized to endosomal compartments and mediates the transport of several transmembrane cargos. How these complexes are formed however is completely unknown. Here, we have systematically characterised the interactions between human COMMD proteins, and determined structures of *For correspondence: [email protected] (BMC); COMMD proteins using X-ray crystallography and X-ray scattering to provide insights into the [email protected] (RG) underlying mechanisms of homo- and heteromeric assembly. All COMMD proteins possess an a- helical N-terminal domain, and a highly conserved C-terminal domain that forms a tightly † Present address: Institute of interlocked dimeric structure responsible for COMMD-COMMD interactions. The COMM domains Structural and Molecular Biology, also bind directly to components of CCC and mediate non-specific membrane association. Overall Department of Biological these studies show that COMMD proteins function as obligatory dimers with conserved domain Sciences, Birkbeck College, London, United Kingdom architectures. -
Transcriptome-Wide Profiling of Multiple RNA Modifications Simultaneously at Single-Base Resolution,” by Vahid Khoddami, Archana Yerra, Timothy L
Correction BIOCHEMISTRY, CHEMISTRY Correction for “Transcriptome-wide profiling of multiple RNA modifications simultaneously at single-base resolution,” by Vahid Khoddami, Archana Yerra, Timothy L. Mosbruger, Aaron M. Fleming, Cynthia J. Burrows, and Bradley R. Cairns, which was first published March 14, 2019; 10.1073/pnas.1817334116 (Proc Natl Acad Sci USA 116:6784–6789). The authors note that the following statement should be added to the Acknowledgments: “This work was also supported by Grant R01 GM093099 from the NIH/National Institute of General Medical Sciences (to C.J.B.).” Published under the PNAS license. Published online April 22, 2019. www.pnas.org/cgi/doi/10.1073/pnas.1905628116 9136 | PNAS | April 30, 2019 | vol. 116 | no. 18 www.pnas.org Downloaded by guest on October 2, 2021 Transcriptome-wide profiling of multiple RNA modifications simultaneously at single-base resolution Vahid Khoddamia,b,c,1,2, Archana Yerrab,c,1, Timothy L. Mosbrugerd, Aaron M. Fleminge, Cynthia J. Burrowse,3, and Bradley R. Cairnsb,c,3 aDepartment of Cell Biology, Harvard Medical School, Boston, MA 02115; bHoward Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, UT 84112; cDepartment of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112; dBioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112; and eDepartment of Chemistry, University of Utah, Salt Lake City, UT 84112 Contributed by Cynthia J. Burrows, January 25, 2019 (sent for review October 9, 2018; reviewed by Juan D. Alfonzo, Thomas Carell, and Peter C. -
MOCHI Enables Discovery of Heterogeneous Interactome Modules in 3D Nucleome
Downloaded from genome.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press MOCHI enables discovery of heterogeneous interactome modules in 3D nucleome Dechao Tian1,# , Ruochi Zhang1,# , Yang Zhang1, Xiaopeng Zhu1, and Jian Ma1,* 1Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA #These two authors contributed equally *Correspondence: [email protected] Contact To whom correspondence should be addressed: Jian Ma School of Computer Science Carnegie Mellon University 7705 Gates-Hillman Complex 5000 Forbes Avenue Pittsburgh, PA 15213 Phone: +1 (412) 268-2776 Email: [email protected] 1 Downloaded from genome.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Abstract The composition of the cell nucleus is highly heterogeneous, with different constituents forming complex interactomes. However, the global patterns of these interwoven heterogeneous interactomes remain poorly understood. Here we focus on two different interactomes, chromatin interaction network and gene regulatory network, as a proof-of-principle, to identify heterogeneous interactome modules (HIMs), each of which represents a cluster of gene loci that are in spatial contact more frequently than expected and that are regulated by the same group of transcription factors. HIM integrates transcription factor binding and 3D genome structure to reflect “transcriptional niche” in the nucleus. We develop a new algorithm MOCHI to facilitate the discovery of HIMs based on network motif clustering in heterogeneous interactomes. By applying MOCHI to five different cell types, we found that HIMs have strong spatial preference within the nucleus and exhibit distinct functional properties. Through integrative analysis, this work demonstrates the utility of MOCHI to identify HIMs, which may provide new perspectives on the interplay between transcriptional regulation and 3D genome organization. -
WO 2012/174282 A2 20 December 2012 (20.12.2012) P O P C T
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2012/174282 A2 20 December 2012 (20.12.2012) P O P C T (51) International Patent Classification: David [US/US]; 13539 N . 95th Way, Scottsdale, AZ C12Q 1/68 (2006.01) 85260 (US). (21) International Application Number: (74) Agent: AKHAVAN, Ramin; Caris Science, Inc., 6655 N . PCT/US20 12/0425 19 Macarthur Blvd., Irving, TX 75039 (US). (22) International Filing Date: (81) Designated States (unless otherwise indicated, for every 14 June 2012 (14.06.2012) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, English (25) Filing Language: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, Publication Language: English DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, (30) Priority Data: KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, 61/497,895 16 June 201 1 (16.06.201 1) US MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 61/499,138 20 June 201 1 (20.06.201 1) US OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, 61/501,680 27 June 201 1 (27.06.201 1) u s SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, 61/506,019 8 July 201 1(08.07.201 1) u s TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.