"Protein Quaternary Structure: Subunit&Ndash;Subunit
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Introduction of Human Telomerase Reverse Transcriptase to Normal Human Fibroblasts Enhances DNA Repair Capacity
Vol. 10, 2551–2560, April 1, 2004 Clinical Cancer Research 2551 Introduction of Human Telomerase Reverse Transcriptase to Normal Human Fibroblasts Enhances DNA Repair Capacity Ki-Hyuk Shin,1 Mo K. Kang,1 Erica Dicterow,1 INTRODUCTION Ayako Kameta,1 Marcel A. Baluda,1 and Telomerase, which consists of the catalytic protein subunit, No-Hee Park1,2 human telomerase reverse transcriptase (hTERT), the RNA component of telomerase (hTR), and several associated pro- 1School of Dentistry and 2Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California teins, has been primarily associated with maintaining the integ- rity of cellular DNA telomeres in normal cells (1, 2). Telomer- ase activity is correlated with the expression of hTERT, but not ABSTRACT with that of hTR (3, 4). Purpose: From numerous reports on proteins involved The involvement of DNA repair proteins in telomere main- in DNA repair and telomere maintenance that physically tenance has been well documented (5–8). In eukaryotic cells, associate with human telomerase reverse transcriptase nonhomologous end-joining requires a DNA ligase and the (hTERT), we inferred that hTERT/telomerase might play a DNA-activated protein kinase, which is recruited to the DNA role in DNA repair. We investigated this possibility in nor- ends by the DNA-binding protein Ku. Ku binds to hTERT mal human oral fibroblasts (NHOF) with and without ec- without the need for telomeric DNA or hTR (9), binds the topic expression of hTERT/telomerase. telomere repeat-binding proteins TRF1 (10) and TRF2 (11), and Experimental Design: To study the effect of hTERT/ is thought to regulate the access of telomerase to telomere DNA telomerase on DNA repair, we examined the mutation fre- ends (12, 13). -
Gene Section Review
Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL INIST-CNRS Gene Section Review XRCC2 (X-ray repair cross complementing 2) Paul R Andreassen, Helmut Hanenberg Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati OH, USA; [email protected] (PRA); Department of Pediatrics III, University Children's Hospital Essen, University Duisburg- Essen, Essen Germany; [email protected] (HH) Published in Atlas Database: November 2017 Online updated version : http://AtlasGeneticsOncology.org/Genes/XRCC2ID334ch7q36.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/69759/11-2017-XRCC2ID334ch7q36.pdf DOI: 10.4267/2042/69759 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology Clinically, the only known FA-U patient in the Abstract world exhibits severe congenital abnormalities, but XRCC2 is one of five somatic RAD51 paralogs, all had not developed, by seven years of age, the bone of which have Walker A and B ATPase motifs. marrow failure and cancer that are often seen in Each of the paralogs, including XRCC2, has a patients from other FA complementation groups. function in DNA double-strand break repair by Keywords homologous recombination (HR). However, their Fanconi anemia, Breast Cancer Susceptibility, individual roles are not as well understood as that Tumor Suppressor, Homologous Recombination, of RAD51 itself. DNA Repair, RAD51 Paralog The XRCC2 protein forms a complex (BCDX2) with three other RAD51 paralogs, RAD51B, RAD51C and RAD51D. It is believed that the Identity BCDX2 complex mediates HR downstream of Other names: FANCU BRCA2 but upstream of RAD51, as XRCC2 is HGNC (Hugo): XRCC2 involved in the assembly of RAD51 into DNA damage foci. -
Biochemistry-2018-Hartman.Pdf
Article Cite This: Biochemistry 2019, 58, 1527−1538 pubs.acs.org/biochemistry Experimental Evaluation of Coevolution in a Self-Assembling Particle Emily C. Hartman,† Marco J. Lobba,† Andrew H. Favor,† Stephanie A. Robinson,† Matthew B. Francis,*,†,‡ and Danielle Tullman-Ercek*,§ † Department of Chemistry, University of California, Berkeley, California 94720-1460, United States ‡ Materials Sciences Division, Lawrence Berkeley National Laboratories, Berkeley, California 94720-1460, United States § Department of Chemical and Biological Engineering, Northwestern University, 2145 Sheridan Road, Technological Institute E136, Evanston, Illinois 60208-3120, United States *S Supporting Information ABSTRACT: Protein evolution occurs via restricted evolutionary paths that are influenced by both previous and subsequent mutations. This effect, termed epistasis, is critical in population genetics, drug resistance, and immune escape; however, the effect of epistasis on the level of protein fitness is less well characterized. We generated and characterized a 6615-member library of all two-amino acid combinations in a highly mutable loop of a virus-like particle. This particle is a model of protein self- assembly and a promising vehicle for drug delivery and imaging. In addition to characterizing the effect of all double mutants on assembly, thermostability, and acid stability, we observed many instances of epistasis, in which combinations of mutations are either more deleterious or more beneficial than expected. These results were used to generate rules governing the effects of multiple mutations on the self-assembly of the virus-like particle. rotein evolution occurs through complex pathways, often have a significant impact on biotechnology in the coming involving nonintuitive leaps between functional var- decades.23,24 To maximize this potential, it is important to P − iants.1 3 These paths include local minima and maxima, in understand how non-native functions can be hindered by which the effect of a given mutation depends entirely on the unanticipated epistatic effects. -
Metabolic Genes.Xlsx
Table S4 Survey of key functional genes with biogeochemical or energetic importance in the genomes of Tardiphaga isolates. The gene list was complied from the FunGen pipeline (http://fungene.cme.msu.edu/) and the authors' own collection. Category Gene Enzyme vice154 vice278 vice304 vice352 C metabolism scd2 esterase / lipase ●●●● C metabolism xylA xylose isomerase ○○○○ One carbon metabolism cooS carbon monoxide dehydrogenase ○○○○ One carbon metabolism pmoA particulate methane monooxygenase A‐subunit ○○○○ One carbon metabolism pxmA1 particulate methane monooxygenase beta subunit ○○○○ One carbon metabolism prk phosphoribulokinase ●●●● One carbon metabolism cbbL ribulose‐bisphosphate carboxylase large subunit ●●●● One carbon metabolism cbbM ribulose‐bisphosphate carboxylase small subunit ●●●● One carbon metabolism smmo soluble methane monooxygenase ●●●● N metabolism amiE aliphatic amidase ●●●● N metabolism amoA ammonia monooxygenase subunit A ○○○○ N metabolism ansA asparaginase ○○○○ N metabolism aspA aspartate ammonia‐lyase ○○○○ N metabolism glsA glutaminase ●●●● N metabolism hutH histidine ammonia‐lyase ○○○○ N metabolism norB nitric oxide reductase ○○○○ N metabolism p450nor nitric oxide reductase (NAD(P), nitrous oxide‐forming) ○○○○ N metabolism nir nitrite reductase ●●●● N metabolism nifH nitrogenase iron protein ○○○○ N metabolism anfD nitrogenase iron‐iron protein, alpha chain ○○○○ N metabolism nifD nitrogenase molybdenum‐iron protein subunit alpha ○○○○ N metabolism vnfD nitrogenase vanadium‐iron protein alpha chain ○○○○ N metabolism nosZ -
Role of Transglutaminase 2 in Cell Death, Survival, and Fibrosis
cells Review Role of Transglutaminase 2 in Cell Death, Survival, and Fibrosis Hideki Tatsukawa * and Kiyotaka Hitomi Cellular Biochemistry Laboratory, Graduate School of Pharmaceutical Sciences, Nagoya University, Tokai National Higher Education and Research System, Nagoya 464-8601, Aichi, Japan; [email protected] * Correspondence: [email protected]; Tel.: +81-52-747-6808 Abstract: Transglutaminase 2 (TG2) is a ubiquitously expressed enzyme catalyzing the crosslink- ing between Gln and Lys residues and involved in various pathophysiological events. Besides this crosslinking activity, TG2 functions as a deamidase, GTPase, isopeptidase, adapter/scaffold, protein disulfide isomerase, and kinase. It also plays a role in the regulation of hypusination and serotonylation. Through these activities, TG2 is involved in cell growth, differentiation, cell death, inflammation, tissue repair, and fibrosis. Depending on the cell type and stimulus, TG2 changes its subcellular localization and biological activity, leading to cell death or survival. In normal unstressed cells, intracellular TG2 exhibits a GTP-bound closed conformation, exerting prosurvival functions. However, upon cell stimulation with Ca2+ or other factors, TG2 adopts a Ca2+-bound open confor- mation, demonstrating a transamidase activity involved in cell death or survival. These functional discrepancies of TG2 open form might be caused by its multifunctional nature, the existence of splicing variants, the cell type and stimulus, and the genetic backgrounds and variations of the mouse models used. TG2 is also involved in the phagocytosis of dead cells by macrophages and in fibrosis during tissue repair. Here, we summarize and discuss the multifunctional and controversial Citation: Tatsukawa, H.; Hitomi, K. roles of TG2, focusing on cell death/survival and fibrosis. -
Every Detail Matters. That Is, How the Interaction Between Gα Proteins and Membrane Affects Their Function
membranes Review Every Detail Matters. That Is, How the Interaction between Gα Proteins and Membrane Affects Their Function Agnieszka Polit * , Paweł Mystek and Ewa Błasiak Department of Physical Biochemistry, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland; [email protected] (P.M.); [email protected] (E.B.) * Correspondence: [email protected]; Tel.: +48-12-6646156 Abstract: In highly organized multicellular organisms such as humans, the functions of an individ- ual cell are dependent on signal transduction through G protein-coupled receptors (GPCRs) and subsequently heterotrimeric G proteins. As most of the elements belonging to the signal transduction system are bound to lipid membranes, researchers are showing increasing interest in studying the accompanying protein–lipid interactions, which have been demonstrated to not only provide the environment but also regulate proper and efficient signal transduction. The mode of interaction between the cell membrane and G proteins is well known. Despite this, the recognition mechanisms at the molecular level and how the individual G protein-membrane attachment signals are interre- lated in the process of the complex control of membrane targeting of G proteins remain unelucidated. This review focuses on the mechanisms by which mammalian Gα subunits of G proteins interact with lipids and the factors responsible for the specificity of membrane association. We summarize recent data on how these signaling proteins are precisely targeted to a specific site in the membrane region by introducing well-defined modifications as well as through the presence of polybasic regions Citation: Polit, A.; Mystek, P.; within these proteins and interactions with other components of the heterocomplex. -
Dimerization and Domain Swapping in G-Protein-Coupled Receptors: a Computational Study Paul R
Dimerization and Domain Swapping in G-Protein-Coupled Receptors: A Computational Study Paul R. Gouldson, Ph.D., Christopher Higgs, Ph.D., Richard E. Smith, B.Sc., Mark K. Dean, B.Sc., George V. Gkoutos, M.Sc., and Christopher A. Reynolds, Ph.D. In recent years there has been an increasing number of swapped dimers and contact dimers as the models used were reports describing G protein-coupled receptor (GPCR) restricted to the helical part of the receptor. However, it is dimerization and heterodimerization. However, the evidence proposed that for the purpose of signalling, the domain on the nature of the dimers and their role in GPCR swapped dimer and the corresponding contact dimer are activation is inconclusive. Consequently, we present here a equivalent. The evolutionary trace analysis suggests that review of our computational studies on G protein-coupled every GPCR family and subfamily (for which sufficient receptor dimerization and domain swapping. The studies sequence data is available) has the potential to dimerize described include molecular dynamics simulations on through this common functional site on helices 5 and 6. The receptor monomers and dimers in the absence of ligand, in evolutionary trace results on the G protein are briefly the presence of an agonist, and in the presence of an described and these are consistent with GPCR dimerization. antagonist (or more precisely an inverse agonist). Two In addition to the functional site on helices 5 and 6, the distinct sequence-based approaches to studying protein evolutionary trace analysis identified a second functional interfaces are also described, namely correlated mutation site on helices 2 and 3. -
Telomerase Catalysis: a Phylogenetically Conserved Reverse Transcriptase
Proc. Natl. Acad. Sci. USA Vol. 95, pp. 8415–8416, July 1998 Commentary Telomerase catalysis: A phylogenetically conserved reverse transcriptase Victoria Lundblad Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 Replication of telomeres, the ends of eukaryotic chromo- replication and maintenance. As a consequence, the first two somes, is the responsibility of the enzyme telomerase. Since its telomerase-associated proteins, p80 and p95, were identified discovery 13 years ago, research on this unusual DNA poly- after purification of the Tetrahymena telomerase complex (15). merase has revealed a series of surprises. The first of these was On the basis of limited sequence similarities with other poly- the realization that information within the enzyme itself merases, p95 was proposed to contain the catalytic active site determines the sequence of its product: a portion of a telom- of this enzyme (15). However, p95 showed no homology to the erase RNA subunit is the template that dictates the nucleotides emerging family of TERT proteins. This presented a potential added onto the telomere (1, 2). The interest in telomere puzzle, invoking the possibility of an alternative class of replication has increased further during the past several years telomerase enzymes that utilized a different catalytic mecha- because of observations indicating that maintenance of telo- nism. mere length by telomerase could provide the molecular basis This possibility has now been laid to rest by two reports in for determining the lifespan of cells in culture (3). this issue, from the Cech and Collins laboratories, showing that The most recent insight has been the discovery that telom- the Tetrahymena telomerase relies on a reverse transcriptase erase is a reverse transcriptase (4, 5), with catalysis provided subunit for catalysis (7, 13). -
A Screen for Saccharomyces Cerevisiae Essential Genes with an Opi- Phenotype
A Screen for Saccharomyces cerevisiae Essential Genes with an Opi‐ Phenotype Bryan Salas‐Santiago and John M. Lopes 1 Department of Microbiology, and Molecular Cellular Biology Graduate Program, University of Massachusetts, Amherst, Massachusetts 01003 1Address for correspondence. University of Massachusetts, 639 North Pleasant St. Amherst, MA 01003. E‐mail: [email protected]. DOI: 10.1534/g3.113.010140 Table S1 List of essential genes with an Opi- phenotype. Gene Aliases Function Subunit of a heterodimeric nuclear SUMO activating enzyme (E1) with Uba2p; activates Smt3p AOS1 RHC31 (SUMO) before its conjugation to proteins (sumoylation) Acetyl-coA synthetase isoform which, along with Acs1p, is the nuclear source of acetyl-coA for ACS2 histone acetylation; mutants affect global transcription ATPase of the CDC48/PAS1/SEC18 (AAA) family, forms a hexameric complex; is essential for AFG2 DRG1 pre-60S maturation and release of several preribosome maturation factors Catalytic component of UDP-GlcNAc transferase, required for the second step of dolichyl-linked ALG13 oligosaccharide synthesis; anchored to the ER membrane via interaction with Alg14p ALG2 Mannosyltransferase that catalyzes two consecutive steps in the N-linked glycosylation pathway Subunit of the ARP2/3 complex, which is required for the motility and integrity of cortical actin ARC40 patches Nuclear actin-related protein involved in chromatin remodeling, component of chromatin- ARP4 ACT3 remodeling enzyme complexes including NuA4 complex CDC11 PSL9 Component of the septin -
Systematic Characterization of Pan-Cancer Mutation Clusters
Research Collection Journal Article Systematic characterization of pan-cancer mutation clusters Author(s): Buljan, Marija; Blattmann, Peter; Aebersold, Ruedi; Boutros, Michael Publication Date: 2018-03-01 Permanent Link: https://doi.org/10.3929/ethz-b-000256182 Originally published in: Molecular Systems Biology 14(3), http://doi.org/10.15252/msb.20177974 Rights / License: Creative Commons Attribution 4.0 International This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library Published online: March 23, 2018 Article Systematic characterization of pan-cancer mutation clusters Marija Buljan1,2 , Peter Blattmann1 , Ruedi Aebersold1,3,* & Michael Boutros2,4,5,** Abstract or single point mutations. Eventually, they all lead to changes in the expression levels or to altered functions of cancer driver genes and Cancer genome sequencing has shown that driver genes can often their products. Analysis of different cancer genomics datasets has be distinguished not only by the elevated mutation frequency but further underscored a high degree of heterogeneity in the mutation also by specific nucleotide positions that accumulate changes at a frequency and spectrum among different cancer types (Garraway & high rate. However, properties associated with a residue’s poten- Lander, 2013; Lawrence et al, 2013) and uncovered a long tail of tial to drive tumorigenesis when mutated have not yet been low-frequency driver mutations (Garraway & Lander, 2013). As a systematically investigated. Here, using a novel methodological corollary, in spite of the great progress in charting mutational events approach, we identify and characterize a compendium of 180 that define different cancer types, the task to distinguish driver and hotspot residues within 160 human proteins which occur with a passenger mutations in an individual genome remains a formidable significant frequency and are likely to have functionally relevant challenge. -
Detecting, Identifying, and Disrupting Protein-Protein Interactions
Detecting, Identifying, and Disrupting Protein-Protein Interactions by Sang-Hyun Park A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Biochemistry) at the UNIVERSITY OF WISCONSIN - MADISON 1999 A dissertation entitled Detecting, Identifying, and Disrupting Protein-Protein Interactions .... ~,. submitted to the Graduate School of the University of Wisconsin-Madison ~ in partial fulfillment of the requirements for the ~J degree of Doctor of Philosophy by Sang-Hyun Park Date of Final Oral Examination: December l3, 1999 Month & Year Degree to be awarded: December 1 9 9 9 May August l-s: **.****************************~********************** ~.Qf.J~_"ion Readers: Signature, Dean of Graduate School -~ '(1fvti6.5- ~(M~/ifH i ACKNOWLEDGMENTS I am grateful to James Hu, Jordan Tang and Martin Chalfie for providing bacterial strains and plasmids. I also thank Chiwook Park for providing the wild-type RNase A used in Chapter 3. Ronald Raines has been a superior advisor. I thank Ron for his support for my study. He allowed for the freedom of creativity and the freedom of work hour. Genetic selection and screens developed in this thesis owes a lot to frustrations with the yeast two-hybrid screening on which I spent the first two years of my graduate study. This thesis was partially supported by a Korean Government Fellowship for Overseas Study. I must thank my family for their patience and support for my studying abroad. [ cannot thank enough my wife, Nam-Sook Baik, who has endured a great deal of agony and joy together with me throughout the days in Madison. [ want to say sorry to my son, Albert (~ ~), for my occasional absence from him when he needed me. -
NCCN Guidelines®) Genetic/Familial High-Risk Assessment: Colorectal
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Genetic/Familial High-Risk Assessment: Colorectal Version 3.2017 — October 10, 2017 NCCN.org Continue Version 3.2017, 10/10/17 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. NCCN Guidelines Version 3.2017 Panel Members NCCN Guidelines Index Table of Contents Genetic/Familial High-Risk Assessment: Colorectal Discussion * Dawn Provenzale, MD, MS/Chair ¤ Þ Michael J. Hall, MD, MS † ∆ Robert J. Mayer, MD † Þ Duke Cancer Institute Fox Chase Cancer Center Dana-Farber/Brigham and Women’s Cancer Center * Samir Gupta, MD/Vice-chair ¤ Amy L. Halverson, MD ¶ UC San Diego Moores Cancer Center Robert H. Lurie Comprehensive Cancer Reid M. Ness, MD, MPH ¤ Center of Northwestern University Vanderbilt-Ingram Cancer Center Dennis J. Ahnen, MD ¤ University of Colorado Cancer Center Stanley R. Hamilton, MD ≠ Scott E. Regenbogen, MD ¶ The University of Texas University of Michigan Travis Bray, PhD ¥ MD Anderson Cancer Center Comprehensive Cancer Center Hereditary Colon Cancer Foundation Heather Hampel, MS, CGC ∆ Niloy Jewel Samadder, MD ¤ Daniel C. Chung, MD ¤ ∆ The Ohio State University Comprehensive Huntsman Cancer Institute at the Massachusetts General Hospital Cancer Center - James Cancer Hospital University of Utah Cancer Center and Solove Research Institute Moshe Shike, MD ¤ Þ Gregory Cooper, MD ¤ Jason B. Klapman, MD ¤ Memorial Sloan Kettering Cancer Center Case Comprehensive Cancer Center/ Moffitt Cancer Center University Hospitals Seidman Cancer Thomas P. Slavin Jr, MD ∆ Center and Cleveland Clinic Taussig David W. Larson, MD, MBA¶ City of Hope Comprehensive Cancer Institute Mayo Clinic Cancer Center Cancer Center Dayna S.