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ANNUAL REVIEW 1 October 2005–30 September
WELLCOME TRUST ANNUAL REVIEW 1 October 2005–30 September 2006 ANNUAL REVIEW 2006 The Wellcome Trust is the largest charity in the UK and the second largest medical research charity in the world. It funds innovative biomedical research, in the UK and internationally, spending around £500 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing. www.wellcome.ac.uk THE WELLCOME TRUST The Wellcome Trust is the largest charity in the UK and the second largest medical research charity in the world. 123 CONTENTS BOARD OF GOVERNORS 2 Director’s statement William Castell 4 Advancing knowledge Chairman 16 Using knowledge Martin Bobrow Deputy Chairman 24 Engaging society Adrian Bird 30 Developing people Leszek Borysiewicz 36 Facilitating research Patricia Hodgson 40 Developing our organisation Richard Hynes 41 Wellcome Trust 2005/06 Ronald Plasterk 42 Financial summary 2005/06 Alastair Ross Goobey 44 Funding developments 2005/06 Peter Smith 46 Streams funding 2005/06 Jean Thomas 48 Technology Transfer Edward Walker-Arnott 49 Wellcome Trust Genome Campus As at January 2007 50 Public Engagement 51 Library and information resources 52 Advisory committees Images 1 Surface of the gut. 3 Zebrafish. 5 Cells in a developing This Annual Review covers the 2 Young children in 4 A scene from Y fruit fly. Wellcome Trust’s financial year, from Kenya. Touring’s Every Breath. 6 Data management at the Sanger Institute. 1 October 2005 to 30 September 2006. CONTENTS 1 45 6 EXECUTIVE BOARD MAKING A DIFFERENCE Developing people: To foster a Mark Walport The Wellcome Trust’s mission is research community and individual Director to foster and promote research with researchers who can contribute to the advancement and use of knowledge Ted Bianco the aim of improving human and Director of Technology Transfer animal health. -
A Genetic Screen Identifies the Triple T Complex Required for DNA Damage Signaling and ATM and ATR Stability
Downloaded from genesdev.cshlp.org on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press A genetic screen identifies the Triple T complex required for DNA damage signaling and ATM and ATR stability Kristen E. Hurov, Cecilia Cotta-Ramusino, and Stephen J. Elledge1 Howard Hughes Medical Institute and Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA In response to DNA damage, cells activate a complex signal transduction network called the DNA damage response (DDR). To enhance our current understanding of the DDR network, we performed a genome-wide RNAi screen to identify genes required for resistance to ionizing radiation (IR). Along with a number of known DDR genes, we discovered a large set of novel genes whose depletion leads to cellular sensitivity to IR. Here we describe TTI1 (Tel two-interacting protein 1) and TTI2 as highly conserved regulators of the DDR in mammals. TTI1 and TTI2 protect cells from spontaneous DNA damage, and are required for the establishment of the intra-S and G2/M checkpoints. TTI1 and TTI2 exist in multiple complexes, including a 2-MDa complex with TEL2 (telomere maintenance 2), called the Triple T complex, and phosphoinositide-3-kinase-related protein kinases (PIKKs) such as ataxia telangiectasia-mutated (ATM). The components of the TTT complex are mutually dependent on each other, and act as critical regulators of PIKK abundance and checkpoint signaling. [Keywords: TTI1; TEL2; TTI2; PIKK; TTT complex; IR sensitivity] Supplemental material is available at http://www.genesdev.org. Received April 5, 2010; revised version accepted July 22, 2010. -
Holliday Junction Processing Enzymes in Eukaryotes. by Anthony John
Holliday junction processing enzymes in eukaryotes. By Anthony John Keeley Thesis submitted to the University of London, for the degree of Doctor of Philosophy, September 1999 ProQuest Number: 10609126 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 10609126 Published by ProQuest LLC(2017). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 ACKNOWLEDGMENTS I would like to acknowledge some of the people that without their kind help and generosity this work would have been difficult. Firstly I would like to thank members of the laboratory group, Fikret for his help, tutoring in yeast genetics, some improved methods and some long coffee breaks explaining the finer details of recombination. Judit for her help in the laboratory and always having a spare lane on a gel and Mark for his assistance with sequencing gels. I would also like to thank the other members of staff at UCL for their help and positive response to favours, Jeremy Hioms’s group, Peter Piper’s group, Laurence Pearl’s group, David Saggerson’s group, Liz Shephard’s group, Jeremy Brockes’s group and Peter Shepherd’s group. -
Bayesian Hierarchical Modeling of High-Throughput Genomic Data with Applications to Cancer Bioinformatics and Stem Cell Differentiation
BAYESIAN HIERARCHICAL MODELING OF HIGH-THROUGHPUT GENOMIC DATA WITH APPLICATIONS TO CANCER BIOINFORMATICS AND STEM CELL DIFFERENTIATION by Keegan D. Korthauer A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Statistics) at the UNIVERSITY OF WISCONSIN–MADISON 2015 Date of final oral examination: 05/04/15 The dissertation is approved by the following members of the Final Oral Committee: Christina Kendziorski, Professor, Biostatistics and Medical Informatics Michael A. Newton, Professor, Statistics Sunduz Kele¸s,Professor, Biostatistics and Medical Informatics Sijian Wang, Associate Professor, Biostatistics and Medical Informatics Michael N. Gould, Professor, Oncology © Copyright by Keegan D. Korthauer 2015 All Rights Reserved i in memory of my grandparents Ma and Pa FL Grandma and John ii ACKNOWLEDGMENTS First and foremost, I am deeply grateful to my thesis advisor Christina Kendziorski for her invaluable advice, enthusiastic support, and unending patience throughout my time at UW-Madison. She has provided sound wisdom on everything from methodological principles to the intricacies of academic research. I especially appreciate that she has always encouraged me to eke out my own path and I attribute a great deal of credit to her for the successes I have achieved thus far. I also owe special thanks to my committee member Professor Michael Newton, who guided me through one of my first collaborative research experiences and has continued to provide key advice on my thesis research. I am also indebted to the other members of my thesis committee, Professor Sunduz Kele¸s,Professor Sijian Wang, and Professor Michael Gould, whose valuable comments, questions, and suggestions have greatly improved this dissertation. -
Modulating Mistranslation Potential of Trnaser in Saccharomyces Cerevisiae
HIGHLIGHTED ARTICLE | INVESTIGATION Modulating Mistranslation Potential of tRNASer in Saccharomyces cerevisiae Matthew D. Berg,*,1 Yanrui Zhu,* Julie Genereaux,* Bianca Y. Ruiz,† Ricard A. Rodriguez-Mias,† Tyler Allan,* Alexander Bahcheli,* Judit Villén,† and Christopher J. Brandl*,1 *Department of Biochemistry, The University of Western Ontario, London, Ontario N6A 5C1, Canada and †Department of Genome Sciences, University of Washington, Seattle, Washington 98195 ORCID IDs: 0000-0002-7924-9241 (M.D.B.); 0000-0002-1005-1739 (J.V.); 0000-0001-8015-9668 (C.J.B.) ABSTRACT Transfer RNAs (tRNAs) read the genetic code, translating nucleic acid sequence into protein. For tRNASer the anticodon does not specify its aminoacylation. For this reason, mutations in the tRNASer anticodon can result in amino acid substitutions, a process called mistranslation. Previously, we found that tRNASer with a proline anticodon was lethal to cells. However, by incorporating secondary mutations into the tRNA, mistranslation was dampened to a nonlethal level. The goal of this work was to identify second-site substitutions in tRNASer that modulate mistranslation to different levels. Targeted changes to putative identity elements led to total loss of tRNA function or significantly impaired cell growth. However, through genetic selection, we identified 22 substi- tutions that allow nontoxic mistranslation. These secondary mutations are primarily in single-stranded regions or substitute G:U base pairs for Watson–Crick pairs. Many of the variants are more toxic at low temperature and upon impairing the rapid tRNA decay pathway. We suggest that the majority of the secondary mutations affect the stability of the tRNA in cells. The temperature sensitivity of the tRNAs allows conditional mistranslation. -
Genetic Analysis of Over One Million People Identifies 535 New Loci Associated with Blood 2 Pressure Traits
1 Genetic analysis of over one million people identifies 535 new loci associated with blood 2 pressure traits. 3 4 Table of Contents 5 SUPPLEMENTARY TABLES LEGENDS……………………………………………………………………………….…….3 6 SUPPLEMENTARY FIGURES LEGENDS ........................................................................................ 6 7 SUPPLEMENTARY METHODS ................................................................................................... 10 8 1. UK Biobank data .................................................................................................................................... 10 9 2. UKB Quality Control ............................................................................................................................... 10 10 3. Phenotypic data ..................................................................................................................................... 11 11 4. UKB analysis ........................................................................................................................................... 11 12 5. Genomic inflation and confounding ....................................................................................................... 12 13 6. International Consortium for Blood Pressure (ICBP) GWAS .................................................................... 12 14 7. Meta-analyses of discovery datasets ..................................................................................................... 13 15 8. Linkage Disequilibrium calculations ...................................................................................................... -
Sexual Dimorphism in Brain Transcriptomes of Amami Spiny Rats (Tokudaia Osimensis): a Rodent Species Where Males Lack the Y Chromosome Madison T
Ortega et al. BMC Genomics (2019) 20:87 https://doi.org/10.1186/s12864-019-5426-6 RESEARCHARTICLE Open Access Sexual dimorphism in brain transcriptomes of Amami spiny rats (Tokudaia osimensis): a rodent species where males lack the Y chromosome Madison T. Ortega1,2, Nathan J. Bivens3, Takamichi Jogahara4, Asato Kuroiwa5, Scott A. Givan1,6,7,8 and Cheryl S. Rosenfeld1,2,8,9* Abstract Background: Brain sexual differentiation is sculpted by precise coordination of steroid hormones during development. Programming of several brain regions in males depends upon aromatase conversion of testosterone to estrogen. However, it is not clear the direct contribution that Y chromosome associated genes, especially sex- determining region Y (Sry), might exert on brain sexual differentiation in therian mammals. Two species of spiny rats: Amami spiny rat (Tokudaia osimensis) and Tokunoshima spiny rat (T. tokunoshimensis) lack a Y chromosome/Sry, and these individuals possess an XO chromosome system in both sexes. Both Tokudaia species are highly endangered. To assess the neural transcriptome profile in male and female Amami spiny rats, RNA was isolated from brain samples of adult male and female spiny rats that had died accidentally and used for RNAseq analyses. Results: RNAseq analyses confirmed that several genes and individual transcripts were differentially expressed between males and females. In males, seminal vesicle secretory protein 5 (Svs5) and cytochrome P450 1B1 (Cyp1b1) genes were significantly elevated compared to females, whereas serine (or cysteine) peptidase inhibitor, clade A, member 3 N (Serpina3n) was upregulated in females. Many individual transcripts elevated in males included those encoding for zinc finger proteins, e.g. -
Saccharomyces Cerevisiae Tti2 Regulates PIKK Proteins and Stress Response
INVESTIGATION Saccharomyces cerevisiae Tti2 Regulates PIKK Proteins and Stress Response Kyle S. Hoffman,* Martin L. Duennwald,† Jim Karagiannis,‡ Julie Genereaux,* Alexander S. McCarton,* and Christopher J. Brandl*,1 *Department of Biochemistry and †Department of Pathology, Schulich School of Medicine and Dentistry, and ‡Department of Biology, The University of Western Ontario, London, Ontario, N6A5C1 Canada ABSTRACT The TTT complex is composed of the three essential proteins Tel2, Tti1, and Tti2. The complex KEYWORDS is required to maintain steady state levels of phosphatidylinositol 3-kinase-related kinase (PIKK) proteins, TTT complex including mTOR, ATM/Tel1, ATR/Mec1, and TRRAP/Tra1, all of which serve as regulators of critical cell PIKK proteins signaling pathways. Due to their association with heat shock proteins, and with newly synthesized PIKK heat shock peptides, components of the TTT complex may act as cochaperones. Here, we analyze the consequences of response depleting the cellular level of Tti2 in Saccharomyces cerevisiae. We show that yeast expressing low levels of chaperone Tti2 are viable under optimal growth conditions, but the cells are sensitive to a number of stress conditions protein that involve PIKK pathways. In agreement with this, depleting Tti2 levels decreased expression of Tra1, expression Mec1, and Tor1, affected their localization and inhibited the stress responses in which these molecules are involved. Tti2 expression was not increased during heat shock, implying that it does not play a general role in the heat shock response. However, steady state levels of Hsp42 increase when Tti2 is depleted, and tti2L187P has a synthetic interaction with exon 1 of the human Huntingtin gene containing a 103 residue polyQ sequence, suggesting a general role in protein quality control. -
Current State of Mtor Targeting in Human Breast Cancer UMAR WAZIR 1,2 , ALI WAZIR 3, ZUBAIR S
CANCER GENOMICS & PROTEOMICS 11 : 167-174 (2014) Review Current State of mTOR Targeting in Human Breast Cancer UMAR WAZIR 1,2 , ALI WAZIR 3, ZUBAIR S. KHANZADA 4, WEN G. JIANG 4, ANUP K. SHARMA 2 and KEFAH MOKBEL 1,2 1The London Breast Institute, Princess Grace Hospital, London, U.K.; 2Department of Breast Surgery, St. George’s Hospital and Medical School, University of London, London, U.K.; 3Aga Khan University, Karachi, Pakistan; 4Cardiff University-Peking University Cancer Institute (CUPUCI), University Department of Surgery, Cardiff University School of Medicine, Cardiff University, Cardiff, Wales, U.K. Abstract. Background/Aim: The mammalian, or Subsequently, it was found to have immunosuppressive mechanistic, target of rapamycin (mTOR) pathway has been properties, and is currently used therapeutically in renal implicated in several models of human oncogenesis. transplant patients. Like tacrolimus and cyclosporine, it Research in the role of mTOR in human oncogenesis affects the actions of interlekin-2 (IL-2). Unlike tacrolimus, remains a field of intense activity. In this mini-review, we which reduces IL-2 transcription by T-cells, sirolimus intend to recount our current understanding of the mTOR inhibits the proliferative effects of IL-2 on T-cells (3). In pathway, its interactions, and its role in human mammalian models, rapamycin was known to form a carcinogenesis in general, and breast cancer in particular. complex with FK506 binding protein 1A, 12 kDa Materials and Methods: We herein outline the discrete (FKBP12), which interacts with the mammalian, or components of the two complexes of mTOR, and attempt to mechanistic, target of rapamycin (mTOR) subunit of define their distinct roles and interactions. -
Crystallography in the News Product Spotlight
- view this in your browser - Protein Crystallography Newsletter Volume 5, No. 9, September 2013 Crystallography in the news In this issue: September 4, 2013. Computer-designed proteins that can recognize and interact with small biological molecules are now a reality. Scientists have succeeded in creating a Crystallography in the news protein molecule that can be programmed to unite with three different steroids. Crystallographers in the news September 5, 2013. While on sabbatical at the Weizmann Institute of Science in 1993, Product spotlight: Minstrel's asymmetric lighting Paul H. Axelsen—currently a professor at the University of Pennsylvania's Perelman School Lab spotlight: Pearl lab of Medicine—helped figure out how a key enzyme plays a role in communication between Useful links for crystallography certain kinds of nerve cells—the very process that sarin gas interferes with so Webinar: crystallization catastrophically. Survey of the month September 11, 2013. By taking advantage of the fact that our body proteins and robot Science video of the month arms both move in a similar way, the department of mechanical engineering of the ECM delegates raise £1376 for Cancer Research UK UPV/EHU-University of the Basque Country has developed a program to simulate protein movements. Monthly crystallographic papers Book review September 13, 2013. The Royal Swedish Academy of Sciences has awarded the Gregori Aminoff Prize in Crystallography 2014 to Yigong Shi from Tsinghua Univ. in Beijing, China for his "groundbreaking crystallographic studies of proteins and protein complexes that Crystallographers in the News regulate programmed cell death." Max Perutz Prize September 16, 2013. Stopping short of a merger, the nonprofit Hauptman-Woodward The European Crystallographic Medical Research Institute is negotiating with the University at Buffalo School of Medicine Association has awarded the seventh & Biomedical Sciences to change the way the organization and its scientists are Max Perutz Prize to Prof. -
BRCT Domains of the DNA Damage Checkpoint Proteins
RESEARCH COMMUNICATION BRCT domains of the DNA damage checkpoint proteins TOPBP1/Rad4 display distinct specificities for phosphopeptide ligands Matthew Day1, Mathieu Rappas1†, Katie Ptasinska2, Dominik Boos3, Antony W Oliver1*, Laurence H Pearl1* 1Cancer Research UK DNA Repair Enzymes Group, Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, United Kingdom; 2Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, United Kingdom; 3Fakulta¨ t fu¨ r Biologie, Universita¨ t Duisburg-Essen, Germany, United Kingdom Abstract TOPBP1 and its fission yeast homologue Rad4, are critical players in a range of DNA replication, repair and damage signalling processes. They are composed of multiple BRCT domains, some of which bind phosphorylated motifs in other proteins. They thus act as multi-point adaptors bringing proteins together into functional combinations, dependent on post-translational modifications downstream of cell cycle and DNA damage signals. We have now structurally and/or biochemically characterised a sufficient number of high-affinity complexes for the conserved N-terminal region of TOPBP1 and Rad4 with diverse phospho-ligands, including human RAD9 and Treslin, and Schizosaccharomyces pombe Crb2 and Sld3, to define the determinants of BRCT domain specificity. We use this to identify and characterise previously unknown phosphorylation- *For correspondence: dependent TOPBP1/Rad4-binding motifs in human RHNO1 and the fission yeast homologue of [email protected] MDC1, Mdb1. These results provide important insights into how multiple BRCT domains within (AWO); TOPBP1/Rad4 achieve selective and combinatorial binding of their multiple partner proteins. [email protected] (LHP) Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. -
Molecular Evolution in Immune Genes Across the Avian Tree of Life Cambridge.Org/Pao
Parasitology Open Molecular evolution in immune genes across the avian tree of life cambridge.org/pao Diana C. Outlaw1, V. Woody Walstrom1, Haley N. Bodden1, Chuan-yu Hsu2, Mark Arick II2 and Daniel G. Peterson2 Research Article 1Department of Biological Sciences, Mississippi State University, PO Box GY, Mississippi State, MS 39762, USA and Cite this article: Outlaw DC, Walstrom VW, 2Institute for Genomics, Biocomputing & Biotechnology, Mississippi State University, 2 Research Boulevard, Box Bodden HN, Hsu Chuan-yu, Arick II M, Peterson 9627, Starkville, MS 39759, USA DG (2019). Molecular evolution in immune genes across the avian tree of life. Parasitology Open 5, e3, 1–9. https://doi.org/10.1017/ Abstract pao.2019.3 All organisms encounter pathogens, and birds are especially susceptible to infection by mal- Received: 11 July 2018 aria parasites and other haemosporidians. It is important to understand how immune genes, Revised: 22 February 2019 primarily innate immune genes which are the first line of host defense, have evolved across Accepted: 22 February 2019 birds, a highly diverse group of tetrapods. Here, we find that innate immune genes are highly Key words: conserved across the avian tree of life and that although most show evidence of positive or Malaria parasites; haemosporidians; birds; diversifying selection within specific lineages or clades, the number of sites is often propor- molecular evolution; immune genes; innate tionally low in this broader context of putative constraint. Rather, evidence shows a much immunity; bird transcriptome higher level of negative or purifying selection in these innate immune genes – rather than – ’ Author for correspondence: adaptive immune genes which is consistent with birds long coevolutionary history with Diana C.