DOCSLIB.ORG

Mitochondria–Nucleus Network for Genome Stability

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Mitochondria–Nucleus Network for Genome Stability View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Free Radical Biology and Medicine 82 (2015) 73–104 Contents lists available at ScienceDirect Free Radical Biology and Medicine journal homepage: www.elsevier.com/locate/freeradbiomed Review Article Mitochondria–nucleus network for genome stability Aneta Kaniak-Golik, Adrianna Skoneczna n Laboratory of Mutagenesis and DNA Repair, Institute of Biochemistry and Biophysics, Polish Academy of Science, 02-106 Warsaw, Poland article info abstract Article history: The proper functioning of the cell depends on preserving the cellular genome. In yeast cells, a limited Received 18 September 2014 number of genes are located on mitochondrial DNA. Although the mechanisms underlying nuclear Received in revised form genome maintenance are well understood, much less is known about the mechanisms that ensure 25 November 2014 mitochondrial genome stability. Mitochondria influence the stability of the nuclear genome and vice Accepted 13 January 2015 versa. Little is known about the two-way communication and mutual influence of the nuclear and Available online 30 January 2015 mitochondrial genomes. Although the mitochondrial genome replicates independent of the nuclear Keywords: genome and is organized by a distinct set of mitochondrial nucleoid proteins, nearly all genome stability Genome maintenance mechanisms responsible for maintaining the nuclear genome, such as mismatch repair, base excision 0 rho repair, and double-strand break repair via homologous recombination or the nonhomologous end- Oxidative stress joining pathway, also act to protect mitochondrial DNA. In addition to mitochondria-specificDNA Iron–sulfur cluster polymerase γ, the polymerases α, η, ζ, and Rev1 have been found in this organelle. A nuclear genome Heme protein Membrane potential instability phenotype results from a failure of various mitochondrial functions, such as an electron DNA damage transport chain activity breakdown leading to a decrease in ATP production, a reduction in the DNA repair mitochondrial membrane potential (ΔΨ), and a block in nucleotide and amino acid biosynthesis. The Protein assembly loss of ΔΨ inhibits the production of iron–sulfur prosthetic groups, which impairs the assembly of Fe–S Metal toxicity proteins, including those that mediate DNA transactions; disturbs iron homeostasis; leads to oxidative stress; and perturbs wobble tRNA modification and ribosome assembly, thereby affecting translation and leading to proteotoxic stress. In this review, we present the current knowledge of the mechanisms that govern mitochondrial genome maintenance and demonstrate ways in which the impairment of mitochondrial function can affect nuclear genome stability. & 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Contents Introduction............................................................................................................. 74 Maintenance of the mitochondrial genome. 74 How is the ability to maintain stable mitochondrial DNA determined in S. cerevisiae cells?. 74 Mitochondrial nucleoid proteins in S. cerevisiae . 76 Replication of yeast mitochondrial DNA. 77 Other mitochondrial DNA polymerases . 78 Mitochondrial base excision repair (mtBER) . 79 Short-patch BER is mediated by monofunctional and bifunctional glycosylases . 79 Long-patch BER. 82 Mitochondrial mismatch repair and homologous recombination in mitochondria . 82 Msh1-dependent pathway . 82 Abbreviations: used: AP, apurinic/apyrimidinic, i.e., abasic; BER, base excision repair; DSB, DNA double-strand break; 50-dRP, 50-deoxyribose phosphate; CIA, cytosolic iron– sulfur protein assembly; DG, DNA glycosylase; DRM(D), direct repeat-mediated (deletion); ETC, electron transport chain; HR, homologous recombination; ISC, iron–sulfur cluster; LP BER, long-patch BER; MDR, multidrug resistance; MEPS, minimum efficiency processing segment; MMS, methyl methanesulfonate; NHEJ, nonhomologous end- joining pathway; 30-PUA, 30-phospho-α,β-unsaturated aldehyde; RCR, rolling-circle replication; RDR, recombination-dependent replication; ROS, reactive oxygen species; SP BER, short-patch BER; SSA, single-strand annealing; SSB, DNA single-strand break; TCA, tricarboxylic acid cycle, citric acid cycle, Krebs cycle; TLS, translesion synthesis; ΔΨ, mitochondrial membrane potential n Corresponding author. E-mail address: [email protected] (A. Skoneczna). http://dx.doi.org/10.1016/j.freeradbiomed.2015.01.013 0891-5849/& 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 74 A. Kaniak-Golik, A. Skoneczna / Free Radical Biology and Medicine 82 (2015) 73–104 New findings on mitochondrial recombination pathways in yeast cells . 83 Degradation of mtDNA in the network of mtDNA maintenance pathways . 84 Mitochondrial influence on the nuclear genome. 84 Mutations that affect both the mitochondrial and the nuclear genomes . 84 Mutations that perturb the mitochondrial and nuclear genomes in various ways . 85 Mutations that impair mitochondrial functions are important for nuclear genome maintenance . 85 Altered function of the electron transport chain (ETC) can provoke nuclear genome instability . 85 Impaired iron–sulfur cluster production leads to nuclear genome rearrangements . 86 Abnormal dNTP pool size, altered bias, or changed cellular distribution often leads to mutagenesis and/or chromosomal instability . 87 Metal homeostasis disruption impairs prosthetic group creation to influence genome stability . 91 Detoxification and the stress response capacity of mitochondria prevent genotoxic stress and thereby help preserve the genome. 96 Apoptosis failure leads to genome instability . 98 Mitochondrial genome maintenance ensures functional mitochondria and contributes to nuclear genome stability. 99 Conclusions.............................................................................................................99 Acknowledgments. 99 References..............................................................................................................99 Introduction Maintenance of the mitochondrial genome Mitochondria are double-membrane-bound organelles that are α How is the ability to maintain stable mitochondrial DNA determined thought to have evolved from endosymbiotic -proteobacteria and in S. cerevisiae cells? that are essential for the viability of eukaryotic cells. Mitochondria perform a variety of functions: produce bulk cellular ATP through the Before describing the mtDNA maintenance pathways that function energy conversion reactions of oxidative phosphorylation and the in yeast cells, we will introduce a few terms that are specificto tricarboxylic acid cycle; maintain and express the residual mitochon- S. cerevisiae mitochondrial genetics and describe the nonrespiratory drial genome that is required for oxidative phosphorylation; perform reporter gene that was engineered into the yeast mitochondrial important steps of heme biosynthesis, amino acid biosynthesis, genome and shown to be a useful tool for assaying mtDNA stability nucleotide biosynthesis, the urea cycle, and fatty acid metabolism; in this organism. Because S. cerevisiae cells remain viable upon the þ and participate in apoptosis and reactive oxygen species production. loss of functional mtDNA, known as the rho mitochondrial genome, the so-called cytoplasmic petite mutants, i.e., nonrespiring clones that Mitoproteomics studies have indicated that there are ca. 1000 form minute colonies on standard glucose-limited medium, can be mitochondrial proteins in cells of the yeast Saccharomyces cerevisiae isolated easily (reviewed in [13]). These mutants arise from either [1,2] and ca. 1500 proteins in human mitochondria [3].Onlyasmall extensive deletions of mtDNA followed by reamplification of the fraction of these proteins is encoded by mitochondrial genomes, and remaining fragment (rhoÀ genomes/mutants) or a complete loss of this group primarily includes proteins involved in oxidative phos- mtDNA (rho0 mutants). Therefore, at least three rho genotypes are phorylation and ATP synthesis (8 proteins in yeast mitochondria and possible: rhoþ (wild-type), rhoÀ (partial deletion of the mitochondrial 13 proteins in human mitochondria, because yeast mitochondria lack genome), and rho0 (complete loss of mtDNA). subunits of the respiratory chain complex I that are present in human Although rhoÀ and rho0 petites are phenotypically identical, they mitochondria), as well as rRNA and tRNA genes that are required for probably originate from fundamentally different mechanisms. mitochondrial gene expression. Consequently, the vast majority of Petites with no mtDNA are often produced by a failure to transmit À mitochondrial proteins are encoded by the nuclear genome, synthe- mtDNA to the progeny, whereas rho petites most likely result from sized on cytosolic ribosomes and imported into the mitochondria recombination events that form partially deleted and rearranged mtDNA molecules (reviewed in [13,14]). The petite mutations are [4,5]. None of the mitochondrial functions listed above are essential markedly pleiotropic because the mutants are unable to perform for the viability of S. cerevisiae cells, yet protein import into mitochon- mitochondrial protein synthesis (essential components of the dria is essential [4], highlighting the importance of
Load more

Recommended publications
  • Analysis of Gene Expression Data for Gene Ontology
    ANALYSIS OF GENE EXPRESSION DATA FOR GENE ONTOLOGY BASED PROTEIN FUNCTION PREDICTION A Thesis Presented to The Graduate Faculty of The University of Akron In Partial Fulfillment of the Requirements for the Degree Master of Science Robert Daniel Macholan May 2011 ANALYSIS OF GENE EXPRESSION DATA FOR GENE ONTOLOGY BASED PROTEIN FUNCTION PREDICTION Robert Daniel Macholan Thesis Approved: Accepted: _______________________________ _______________________________ Advisor Department Chair Dr. Zhong-Hui Duan Dr. Chien-Chung Chan _______________________________ _______________________________ Committee Member Dean of the College Dr. Chien-Chung Chan Dr. Chand K. Midha _______________________________ _______________________________ Committee Member Dean of the Graduate School Dr. Yingcai Xiao Dr. George R. Newkome _______________________________ Date ii ABSTRACT A tremendous increase in genomic data has encouraged biologists to turn to bioinformatics in order to assist in its interpretation and processing. One of the present challenges that need to be overcome in order to understand this data more completely is the development of a reliable method to accurately predict the function of a protein from its genomic information. This study focuses on developing an effective algorithm for protein function prediction. The algorithm is based on proteins that have similar expression patterns. The similarity of the expression data is determined using a novel measure, the slope matrix. The slope matrix introduces a normalized method for the comparison of expression levels throughout a proteome. The algorithm is tested using real microarray gene expression data. Their functions are characterized using gene ontology annotations. The results of the case study indicate the protein function prediction algorithm developed is comparable to the prediction algorithms that are based on the annotations of homologous proteins.
    [Show full text]
  • A Yeast Phenomic Model for the Gene Interaction Network Modulating
    Louie et al. Genome Medicine 2012, 4:103 http://genomemedicine.com/content/4/12/103 RESEARCH Open Access A yeast phenomic model for the gene interaction network modulating CFTR-ΔF508 protein biogenesis Raymond J Louie3†, Jingyu Guo1,2†, John W Rodgers1, Rick White4, Najaf A Shah1, Silvere Pagant3, Peter Kim3, Michael Livstone5, Kara Dolinski5, Brett A McKinney6, Jeong Hong2, Eric J Sorscher2, Jennifer Bryan4, Elizabeth A Miller3* and John L Hartman IV1,2* Abstract Background: The overall influence of gene interaction in human disease is unknown. In cystic fibrosis (CF) a single allele of the cystic fibrosis transmembrane conductance regulator (CFTR-ΔF508) accounts for most of the disease. In cell models, CFTR-ΔF508 exhibits defective protein biogenesis and degradation rather than proper trafficking to the plasma membrane where CFTR normally functions. Numerous genes function in the biogenesis of CFTR and influence the fate of CFTR-ΔF508. However it is not known whether genetic variation in such genes contributes to disease severity in patients. Nor is there an easy way to study how numerous gene interactions involving CFTR-ΔF would manifest phenotypically. Methods: To gain insight into the function and evolutionary conservation of a gene interaction network that regulates biogenesis of a misfolded ABC transporter, we employed yeast genetics to develop a ‘phenomic’ model, in which the CFTR-ΔF508-equivalent residue of a yeast homolog is mutated (Yor1-ΔF670), and where the genome is scanned quantitatively for interaction. We first confirmed that Yor1-ΔF undergoes protein misfolding and has reduced half-life, analogous to CFTR-ΔF. Gene interaction was then assessed quantitatively by growth curves for approximately 5,000 double mutants, based on alteration in the dose response to growth inhibition by oligomycin, a toxin extruded from the cell at the plasma membrane by Yor1.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • A Divergent Pumilio Repeat Protein Family for Pre-Rrna Processing and Mrna Localization
    A divergent Pumilio repeat protein family for pre-rRNA processing and mRNA localization Chen Qiua, Kathleen L. McCannb, Robert N. Winea, Susan J. Basergab,c,d,1, and Traci M. Tanaka Halla,1 aEpigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709; and Departments of bGenetics, cMolecular Biophysics and Biochemistry, and dTherapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520 Edited by David Baker, University of Washington, Seattle, WA, and approved November 19, 2014 (received for review April 25, 2014) Pumilio/feminization of XX and XO animals (fem)-3 mRNA-binding cell (15). In addition to these functional differences, it is unclear factor (PUF) proteins bind sequence specifically to mRNA targets how these new PUM repeat proteins would interact with target using a single-stranded RNA-binding domain comprising eight RNA. For example, only six PUM repeats are predicted in Puf-A Pumilio (PUM) repeats. PUM repeats have now been identified in and Puf6, and their RNA base-interacting residues are poorly proteins that function in pre-rRNA processing, including human conserved. Puf-A and yeast Puf6. This is a role not previously ascribed to PUF Vertebrate Puf-A functions appear to be important for diseases proteins. Here we present crystal structures of human Puf-A that and embryonic development, but more knowledge is needed to reveal a class of nucleic acid-binding proteins with 11 PUM repeats connect vertebrate morbidities with molecular mechanisms. Human arranged in an “L”-like shape. In contrast to classical PUF proteins, Puf-A changes localization from predominantly nucleolar to nu- Puf-A forms sequence-independent interactions with DNA or RNA, clear when cells are treated with transcriptional or topoisomerase mediated by conserved basic residues.
    [Show full text]
  • Mitochondrial Genetics
    Mitochondrial genetics Patrick Francis Chinnery and Gavin Hudson* Institute of Genetic Medicine, International Centre for Life, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK Introduction: In the last 10 years the field of mitochondrial genetics has widened, shifting the focus from rare sporadic, metabolic disease to the effects of mitochondrial DNA (mtDNA) variation in a growing spectrum of human disease. The aim of this review is to guide the reader through some key concepts regarding mitochondria before introducing both classic and emerging mitochondrial disorders. Sources of data: In this article, a review of the current mitochondrial genetics literature was conducted using PubMed (http://www.ncbi.nlm.nih.gov/pubmed/). In addition, this review makes use of a growing number of publically available databases including MITOMAP, a human mitochondrial genome database (www.mitomap.org), the Human DNA polymerase Gamma Mutation Database (http://tools.niehs.nih.gov/polg/) and PhyloTree.org (www.phylotree.org), a repository of global mtDNA variation. Areas of agreement: The disruption in cellular energy, resulting from defects in mtDNA or defects in the nuclear-encoded genes responsible for mitochondrial maintenance, manifests in a growing number of human diseases. Areas of controversy: The exact mechanisms which govern the inheritance of mtDNA are hotly debated. Growing points: Although still in the early stages, the development of in vitro genetic manipulation could see an end to the inheritance of the most severe mtDNA disease. Keywords: mitochondria/genetics/mitochondrial DNA/mitochondrial disease/ mtDNA Accepted: April 16, 2013 Mitochondria *Correspondence address. The mitochondrion is a highly specialized organelle, present in almost all Institute of Genetic Medicine, International eukaryotic cells and principally charged with the production of cellular Centre for Life, Newcastle energy through oxidative phosphorylation (OXPHOS).
    [Show full text]
  • 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.
    [Show full text]
  • Pathological Ribonuclease H1 Causes R-Loop Depletion and Aberrant DNA Segregation in Mitochondria
    Pathological ribonuclease H1 causes R-loop depletion PNAS PLUS and aberrant DNA segregation in mitochondria Gokhan Akmana,1, Radha Desaia,1, Laura J. Baileyb, Takehiro Yasukawab,2, Ilaria Dalla Rosaa, Romina Durigona, J. Bradley Holmesb,c, Chloe F. Mossa, Mara Mennunia, Henry Houldend, Robert J. Crouchc, Michael G. Hannad, Robert D. S. Pitceathlyd,e, Antonella Spinazzolaa,3, and Ian J. Holta,3 aMedical Research Council, Mill Hill Laboratory, London NW7 1AA, United Kingdom; bMedical Research Council Mitochondrial Biology Unit, Cambridge CB1 9SY, United Kingdom; cDivision of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; dMedical Research Council Centre for Neuromuscular Diseases, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London WC1N 3BG, United Kingdom; and eDepartment of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, United Kingdom Edited by Douglas Koshland, University of California, Berkeley, CA, and approved June 7, 2016 (received for review January 18, 2016) The genetic information in mammalian mitochondrial DNA is densely Results packed; there are no introns and only one sizeable noncoding, or Analysis of RNA hybridized to mtDNA must contend with the control, region containing key cis-elements for its replication and ready degradation of the RNA during extraction (16). Previous expression. Many molecules of mitochondrial DNA bear a third analysis of fragments of mtDNA encompassing the CR dem- strand of DNA, known as “7S DNA,” which forms a displacement onstrated that they included molecules with 7S DNA, as (D-) loop in the control region.
    [Show full text]
  • Supplementary Material Contents
    Supplementary Material Contents Immune modulating proteins identified from exosomal samples.....................................................................2 Figure S1: Overlap between exosomal and soluble proteomes.................................................................................... 4 Bacterial strains:..............................................................................................................................................4 Figure S2: Variability between subjects of effects of exosomes on BL21-lux growth.................................................... 5 Figure S3: Early effects of exosomes on growth of BL21 E. coli .................................................................................... 5 Figure S4: Exosomal Lysis............................................................................................................................................ 6 Figure S5: Effect of pH on exosomal action.................................................................................................................. 7 Figure S6: Effect of exosomes on growth of UPEC (pH = 6.5) suspended in exosome-depleted urine supernatant ....... 8 Effective exosomal concentration....................................................................................................................8 Figure S7: Sample constitution for luminometry experiments..................................................................................... 8 Figure S8: Determining effective concentration .........................................................................................................
    [Show full text]
  • Genetic Identification of Brain Cell Types Underlying Schizophrenia
    bioRxiv preprint doi: https://doi.org/10.1101/145466; this version posted June 2, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Genetic identification of brain cell types underlying schizophrenia Nathan G. Skene 1 †, Julien Bryois 2 †, Trygve E. Bakken3, Gerome Breen 4,5, James J Crowley 6, Héléna A Gaspar 4,5, Paola Giusti-Rodriguez 6, Rebecca D Hodge3, Jeremy A. Miller 3, Ana Muñoz-Manchado 1, Michael C O’Donovan 7, Michael J Owen 7, Antonio F Pardiñas 7, Jesper Ryge 8, James T R Walters 8, Sten Linnarsson 1, Ed S. Lein 3, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Patrick F Sullivan 2,6 *, Jens Hjerling- Leffler 1 * Affiliations: 1 Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden. 2 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-17177 Stockholm, Sweden. 3 Allen Institute for Brain Science, Seattle, Washington 98109, USA. 4 King’s College London, Institute of Psychiatry, Psychology and Neuroscience, MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre, London, UK. 5 National Institute for Health Research Biomedical Research Centre, South London and Maudsley National Health Service Trust, London, UK. 6 Departments of Genetics, University of North Carolina, Chapel Hill, NC, 27599-7264, USA. 7 MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
    [Show full text]
  • Characterizing Genomic Duplication in Autism Spectrum Disorder by Edward James Higginbotham a Thesis Submitted in Conformity
    Characterizing Genomic Duplication in Autism Spectrum Disorder by Edward James Higginbotham A thesis submitted in conformity with the requirements for the degree of Master of Science Graduate Department of Molecular Genetics University of Toronto © Copyright by Edward James Higginbotham 2020 i Abstract Characterizing Genomic Duplication in Autism Spectrum Disorder Edward James Higginbotham Master of Science Graduate Department of Molecular Genetics University of Toronto 2020 Duplication, the gain of additional copies of genomic material relative to its ancestral diploid state is yet to achieve full appreciation for its role in human traits and disease. Challenges include accurately genotyping, annotating, and characterizing the properties of duplications, and resolving duplication mechanisms. Whole genome sequencing, in principle, should enable accurate detection of duplications in a single experiment. This thesis makes use of the technology to catalogue disease relevant duplications in the genomes of 2,739 individuals with Autism Spectrum Disorder (ASD) who enrolled in the Autism Speaks MSSNG Project. Fine-mapping the breakpoint junctions of 259 ASD-relevant duplications identified 34 (13.1%) variants with complex genomic structures as well as tandem (193/259, 74.5%) and NAHR- mediated (6/259, 2.3%) duplications. As whole genome sequencing-based studies expand in scale and reach, a continued focus on generating high-quality, standardized duplication data will be prerequisite to addressing their associated biological mechanisms. ii Acknowledgements I thank Dr. Stephen Scherer for his leadership par excellence, his generosity, and for giving me a chance. I am grateful for his investment and the opportunities afforded me, from which I have learned and benefited. I would next thank Drs.
    [Show full text]
  • Structure of the Essential MTERF4:NSUN4 Protein Complex Reveals How an MTERF Protein Collaborates to Facilitate Rrna Modification
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Structure Article Structure of the Essential MTERF4:NSUN4 Protein Complex Reveals How an MTERF Protein Collaborates to Facilitate rRNA Modification Elena Yakubovskaya,1,2 Kip E. Guja,1,2 Edison Mejia,1,2 Steven Castano,1 Elena Hambardjieva,1 Woo Suk Choi,1 and Miguel Garcia-Diaz1,* 1Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA 2These authors contributed equally to this work *Correspondence: [email protected] http://dx.doi.org/10.1016/j.str.2012.08.027 SUMMARY nizes a sequence in the mitochondrial tRNA-Leu(UUR) gene, which is downstream and adjacent to the 16S rRNA gene MTERF4 is the first MTERF family member shown to and promotes bidirectional transcriptional termination (Asin- bind RNA and plays an essential role as a regulator of Cayuela et al., 2005; Yakubovskaya et al., 2010). MTERF2 and ribosomal biogenesis in mammalian mitochondria. It MTERF3 have been proposed to associate with mitochondrial forms a complex with the rRNA methyltransferase DNA in a nonsequence-specific manner and regulate mtDNA NSUN4 and recruits it to the large ribosomal subunit. transcription (Park et al., 2007; Roberti et al., 2009; Wenz In this article, we characterize the interaction et al., 2009). Recently, crystal structures of MTERF1 (Jime´ nez-Mene´ ndez between both proteins, demonstrate that MTERF4 et al., 2010; Yakubovskaya et al., 2010) and MTERF3 (Spa˚ hr strongly stimulates the specificity of NSUN4 during et al., 2010) have revealed that these proteins share a unique in vitro methylation experiments, and present the superhelical fold.
    [Show full text]
  • Regulation and Retrograde Coordination of Mitochondrial Gene Expression Adnan Khan Niazi
    Regulation and retrograde coordination of mitochondrial gene expression Adnan Khan Niazi To cite this version: Adnan Khan Niazi. Regulation and retrograde coordination of mitochondrial gene expression. Agri- cultural sciences. Université de Strasbourg, 2013. English. NNT : 2013STRAJ026. tel-00940588 HAL Id: tel-00940588 https://tel.archives-ouvertes.fr/tel-00940588 Submitted on 2 Feb 2014 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. UNIVERSITE DE STRASBOURG THESE DE DOCTORAT Présentée à la FACULTE DES SCIENCES DE LA VIE En vue de l’obtention du titre de DOCTEUR DE L’UNIVERSITE DE STRASBOURG Spécialité : Aspects Moléculaires et Cellulaires de la Biologie Par Adnan Khan NIAZI Régulation et coordination rétrograde de l'expression génétique mitochondriale Regulation and retrograde coordination of mitochondrial gene expression Soutenue le 26 Juin 2013 devant le jury composé de Pr. David MACHEREL (Université d'Angers) Rapporteur externe Pr. Mizuki TAKENAKA (Université de Ulm) Rapporteur externe Dr. Pascale ROMBY (CNRS - Université de Strasbourg) Examinateur Dr. André DIETRICH (CNRS - Université de Strasbourg) Directeur de thèse Membre invité : Frédérique WEBER-LOTFI (Université de Strasbourg) Unité de Recherche Institut de Biologie Moléculaire des Plantes - CNRS UPR2357 Strasbourg, FRANCE Acknowledgements I humbly bow my head before ALLAH, the most beneficent and merciful, whose blessing flourished my thoughts and thrived my ambitions.
    [Show full text]