TELOMERASES Cover art: Model of telomerase extending telomeric DNA (blue) This model is rendered from available crystal and NMR structures of the telomerase RNA (green; 2K95, 2L3E, 1Z31, and 1OQ0), the telomerase reverse transcriptase (TEN, pink; 2B2A; TRBD, light red; RT, red; and CTE, dark red; 3KYL), the H/ACA snoRNP complex (dyskerin, light blue; Gar1, blue; Nop10, sky blue; and Nhp2, dark blue; 2HVY), and the Pot1-Tpp1 complex (yellow, 1XJV and orange, 2I46; respectively) Image provided by Josh D Podlevsky and Julian J.-L Chen (Arizona State University) TELOMERASES Chemistry, Biology, and Clinical Applications Edited by NEAL F LUE Weill Medical College of Cornell University, New York, NY, USA CHANTAL AUTEXIER Departments of Anatomy and Cell Biology, and Medicine, McGill University Bloomfield Centre for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada Copyright Ó 2012 by John Wiley & Sons, Inc All rights reserved Published by John Wiley & Sons, Inc., Hoboken, New Jersey Published simultaneously in Canada No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright.com Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008, or online at http://www.wiley.com/go/permission Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose No warranty may be created or extended by sales representatives or written sales materials The advice and strategies contained herein may not be suitable for your situation You should consult with a professional where appropriate Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762-2974, outside the United States at (317) 572-3993 or fax (317) 572-4002 Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic formats For more information about Wiley products, visit our web site at www.wiley.com Library of Congress Cataloging-in-Publication Data: Telomerases : chemistry, biology, and clinical applications / edited by Neal F Lue, Chantal Autexier – 1st ed p ; cm Includes bibliographical references and index ISBN 978-0-470-59204-5 (hardback) I Lue, F Neal, 1962- II Autexier, Chantal, 1963[DNLM: Telomerase QU 56] 572.80 6–dc23 2011047556 Printed in the United States of America ISBN: 9780470592045 10 CONTENTS Preface vii Contributors ix The Telomerase Complex: An Overview Johanna Mancini and Chantal Autexier Telomerase RNA: Structure, Function, and Molecular Mechanisms 23 Yehuda Tzfati and Julian J.-L Chen TERT Structure, Function, and Molecular Mechanisms 53 Emmanuel Skordalakes and Neal F Lue Telomerase Biogenesis: RNA Processing, Trafficking, and Protein Interactions 79 Tara Beattie and Pascal Chartrand Transcriptional Regulation of Human Telomerase 105 Antonella Farsetti and Yu-Sheng Cong Telomerase Regulation and Telomere-Length Homeostasis 135 Joachim Lingner and David Shore Telomere Structure in Telomerase Regulation 157 Momchil D Vodenicharov and Raymund J Wellinger v vi CONTENTS Off-Telomere Functions of Telomerase 201 Kenkichi Masutomi and William C Hahn Murine Models of Dysfunctional Telomeres and Telomerase 213 Yie Liu and Lea Harrington 10 Cellular Senescence, Telomerase, and Cancer in Human Cells 243 Phillip G Smiraldo, Jun Tang, Jerry W Shay, and Woodring E Wright 11 Telomerase, Retrotransposons, and Evolution 265 Irina R Arkhipova Index 301 PREFACE This year marks the 27th anniversary of the discovery of telomerase In retrospect, even though hints of a special activity needed to maintain linear chromosome ends could be traced to earlier theoretical arguments and experimental observations, it was the exposure of an autoradiogram on Christmas day, 1984 that finally brought the activity into sharp focus and enabled it to be captured, dissected, and manipulated The fascinating story of the discovery of telomerase has been told elsewhere and will not be repeated here Our goal for this volume is instead to take stock of what has been learned about this fascinating reverse transcriptase in the ensuing 27 years, in the hope of providing more impetus for the investigation into its chemistry, biology, and clinical applications If the past 27 years can serve as a guide, than the payoff for the next 27 years of telomerase research would be great indeed We have organized this compendium with a view toward offering integrated discussions of the three aspects of telomerase covered by the subtitle The collection starts with an overview of the telomerase complex, followed by in-depth discussions of the chemistry of its two critical components: TERTand TER The next two chapters highlight the biological regulatory mechanisms that control the synthesis and assembly of the telomerase complex Equally significant are the regulations imposed by the nucleoprotein complex at chromosome ends, the topics of the two ensuing chapters Three more chapters accent studies that bring considerable spotlight to telomerase as a promising target and a useful tool in medical interventions The collection then concludes with an essay that puts telomerase in evolutionary context and illuminates its place in the extraordinarily diverse family of reverse transcriptases Although telomerase research is far from unique in the exploitation of model organisms, it has perhaps uniquely benefited from this approach, as evidenced by the initial discovery of the enzyme in ciliated protozoa, and the demonstration of its vii viii PREFACE importance in chromosome maintenance in budding yeast The proliferation of model system analysis, while arguably indispensable, also made it difficult even for specialists to keep abreast of all the relevant developments, not to say students and investigators newly attracted to a vibrant research field A main objective for authors of this volume, then, is not only to gather significant experimental observations, but also to provide an integrated discussion of each significant topic across different model systems We thank all of the authors for their tremendous efforts in this difficult but admirable endeavor This project would not have taken place without the initial suggestion and expert guidance of Anita Lekwani at Wiley Rebekah Amos and Catherine Odal’s help in shepherding the initial drafts into the final texts is greatly appreciated Finally, we thank our coworkers and colleagues for making the study of telomerase an “endlessly” stimulating and fascinating endeavor NEAL F LUE CHANTAL AUTEXIER CONTRIBUTORS Irina Arkhipova, Josephine Bay Paul Center for Comparative Molecular Biology and Evolution, Marine Biological Laboratory, Woods Hole, MA, USA Chantal Autexier, Departments of Anatomy and Cell Biology, and Medicine, McGill University; Bloomfield Centre for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada Tara Beattie, Southern Alberta Cancer Research Institute and Departments of Biochemistry and Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, Canada Pascal Chartrand, Departement de Biochimie, Universite de Montreal, Montreal, Quebec, Canada Julian J.-L Chen, Department of Chemistry and Biochemistry, and School of Life Sciences, Arizona State University, Tempe, AZ, USA Yu-Sheng Cong, Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou, China Antonella Farsetti, National Research Council (CNR) and Department of Experimental Oncology, Regina Elena Cancer Institute, Rome, Italy William Hahn, Department of Medical Oncology, Dana-Farber Cancer Institute and Departments of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA ix x CONTRIBUTORS Lea Harrington, Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, United Kingdom Joachim Lingner, Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Frontiers in Genetics National Center of Competence in Research, Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne, Switzerland Yie Liu, Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health Baltimore, MD, USA Neal F Lue, Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY, USA Johanna Mancini, Bloomfield Centre for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada Kenkichi Masutomi, Cancer Stem Cell Project, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan; 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a class of non-long-terminal-repeat retrotransposons Mol Cell Biol 8: 114–123 Yamamoto Y, Fujimoto Y, Arai R, Fujie M, Usami S, Yamada T (2003) Retrotransposonmediated restoration of Chlorella telomeres: accumulation of Zepp retrotransposons at termini of newly formed minichromosomes Nucl Acids Res 31: 4646–4653 Yamamoto Y, Noutoshi Y, Fujie M, Usami S, Yamada T (2000) Analysis of double-strandbreak repair by Chlorella retrotransposon Zepp Nucl Acids Symp Ser 44: 101–102 Zakian VA (1995) Telomeres: beginning to understand the end Science 270: 1601–1607 Zhang ML, Tong XJ, Fu XH, Zhou BO, Wang J, Liao XH, Li QJ, Shen N, Ding J, Zhou JQ (2010) Yeast telomerase subunit Est1p has guanine quadruplex-promoting activity that is required for telomere elongation Nat Struct Mol Biol 17: 202–209 Zimmerly S, Guo H, Perlman PS, Lambowitz AM (1995) Group II intron mobility occurs by target DNA-primed reverse transcription Cell 82: 545–554 Zou S, Wright DA, Voytas DF (1995) The Saccharomyces Ty5 retrotransposon family is associated with origins of DNA replication at the telomeres and the silent mating locus HMR Proc Natl Acad Sci USA 92: 920–924 Zou S, Ke N, Kim JM, Voytas DF (1996) The Saccharomyces retrotransposon Ty5 integrates preferentially into regions of silent chromatin at the telomeres and mating loci Genes Dev 10: 634–645 Zou S, Voytas DF (1997) Silent chromatin determines target preference of the Saccharomyces retrotransposon Ty5 Proc Natl Acad Sci USA 94: 7412–7416 INDEX Adineta vaga telomeres, 281 aging and cancer, 123 murine, 215 pathophysiological symptoms, premature-aging syndromes, 215, 225, 255 telomere hypothesis of cellular aging, telomere shortening/replicative, 248, 256 Akt, 118 anaphase promoting complex (APC), 181 aplastic anemia, 9, 70, 203, 215 apoptosis, 4, 114, 115, 119, 121, 214, 217, 219, 245, 254 Arabidopsis thaliana telomeres antisense telomeric transcripts, 1, arthropod telomeres and telomerase, 275–6 ataxia telangiectasia (AT), 215 bacterial chromosomes circular vs linear, 267 retrotransposon, 283 types of linear replicon, 269–70 types of telomeres, 267–9 basic fibroblast growth factor, 117 Bloom syndrome, 219 Bombyx mori telomeres and telomerase non-LTR retrotransposons, 277 telomere-specific retrotransposons, 272 TERT, 55, 278 bone marrow failure syndromes, budding yeast See Saccharomyces cerevisiae CAB box, 5, 40, 82, 86, 146, 148, 215 Caenorhabditis elegans telomeres, 158 Cajal bodies, 82, 83, 86-88, 146, 147 in telomerase assembly and, 215 hTR detected in, 146 TERT foci and hTR-containing, 88 cancer, 7–8, 86, 87, 106, 113, 119, 148, 149, 174, 180, 202, 203, 221 telomerase-based therapy, 248-253 telomeres, 248 dysfunction, in development of, 217–19 Candida albicans telomerase, 41, 138 Candida guilliermondii TER, 80 Candida parapsilosis TER, 80 cartilage-hair hypoplasia (CHH), 10 Telomerases: Chemistry, Biology, and Clinical Applications, First Edition Edited by Neal F Lue and Chantal Autexier Ó 2012 John Wiley & Sons, Inc Published 2012 by John Wiley & Sons, Inc 301 302 CCAAT box, 121 Cdc13 cdc13-1, 143 interaction with Est1, 97, 142, 175, 176 cdc13-2, 176 cell-cycle-dependent trafficking of hTR and hTERT, 87-88 cell-cycle regulation of telomere overhangs, 166–8 cellular oncoproteins regulating hTERT transcription, 113–14 cellular senescence compromised telomerase function leading to, 175 caused by endogenous or exogenous stresses, 244 p53 inactivated, 245 chaperone proteins, 91 Chlamydomonas reinhardtii, RT-like gene, 270, Retrotransposon, 287 Chlorella non-LTR retrotransposon Zepp, 280 chromatin immunoprecipitations (ChIPs), 108 chromosome capping, 161 c-Myc, 113 CRM1-dependent nuclear export signal, 88 C-terminal restriction EN-like (REL), 287 cyclin-dependent kinases (CDKs), 169 cytokines, regulating hTERT transcription, 109, 117–19 DDR machinery, 166 diversity-generating retroelements (DGRs), 283 DNA-binding domain, 67, 111 for telomeric ssDNA, 175 of ETS family, 113 DNA damage, 89, 93, 107, 226 DNA damage-sensing mechanisms, 245 DNA-dependent protein kinase catalytic subunit (DNA-PKcs), 283 in telomere protection, 219 DNA polymerases, 54, 57, 71, 180, 181, 245, 291 DNA repair mechanisms, 245 DNA replication, 2, 43, 141, 148, 158, 162, 179, 181, 225, 226, 256, 267 INDEX DNA–RNA hybrid, DNA synthesis, 29, 56, 64, 159, 205, 245, 289 DNA telomerase-dependent telomere synthesis, 64 DNA transposon, 288 double-stranded DNA break (DSB), 289 double-stranded RNA, 10, 60, 205 Drosophila, 163, 182 chromosomes, 270, 273 genomes, 271, 274 takeover of chromosome ends by retrotransposons in, 270–4 telomeres, organized and maintained in, 163 telomeric retrotransposons, 274–5, 280 Drosophila virilis telomeric retrotransposons, 274–5 Drosophila yakuba telomeric retrotransposons, 274–5 Duchenne muscular dystrophy (DMD), 220 dyskeratosis congenita, 8, 70, 87, 215, 255 dyskerin, 39-40, 93, 94 E6/E6AP, 114 E2F1 promoter, 253 endonuclease-deficient penelope-like retroelements, 281 endoreplication, 228, 229 endothelial NO synthase, 121 eNOS pathway, 106 epidermal growth factor (EGF), 118 epigenetic regulation of hTERT, 119–20 ER/eNOS/HIF trimeric complex, 106 ERs pathway, 106 Est1 binding domain, 40–1 EST genes and proteins, 83, 113–14, 175176, 178 Est1, 96 in telomerase activation, 142 Est3, 96 estrogen response element (ERE), 106, 111 estrogens (E2), 121 eukaryotic retroelements, 271, 285 ever shorter telomeres (ESTs), 40 fission yeast See Schizosaccharomyces pombe fluorescent in situ hybridization (FISH), 83 303 INDEX Fusarium oxysporum, 269 linear pFOXC retroplasmids, 268 GC-rich genomes, 267 geldanamycin, 93 gene therapy, 252 Giardia lamblia telomere-associated non-LTR retrotransposons, 279 structural organization of TERT, 278 telomere-associated retrotransposons of, 272, 280 telomeres in, 279 TERT from, 55 G-quadruplexes, 254, 255 G-rich sequences, 2, 289, 291 growth factors, regulating hTERT transcription, 117–19 HAATI See heterochromatin amplificationmediated and telomerase-independent (HAATI) H/ACA protein complex, 43 Hayflick limit, 243–5 HDAC inhibitors, 119, 120 healing factor concept, hepadnaviruses, 286–9 HeT-A Gag, 273, 274 HeT-A retrotransposition, 273 heterochromatin amplification-mediated and telomerase-independent (HAATI), 1, 10 heterochromatin protein (HP1), 163 heterokaryon-based nucleocytoplasmic shuttling assay, 84 HIFs pathway, 106 HNH motif, 284 Hoogsteen-type hydrogen bonds, 31, 33, 254 HP1- and HAOP-interacting protein (HipHop), 163 HP1-associated protein/Carravagio (HAOP/ Cav), 163 hTERT gene in human tumors and, 107 localization, 106–7 mutant, 70, 89 organization, 106–7 hTERT/hTR interactions, 93 hTERT promoter, 106 binding sites for TRs, 108 chromatin marks, 119 endogenous c-Myc/Max complex on, 120 features of, 107–8 deacetylation of nucleosomes on, 120 hTERT–RMRP complex, 10 hTR/dyskerin/hTERT complex, 93 hTR gene, 254 hTR–hTERT complex, 88 hTR/hTERT gene promoters, 252 human telomerase complex, assembly of, 92 human telomerase RNA intranuclear trafficking, 86–7 processing, and stability, 82–3 human TERT (hTERT), 4, 9, 58, 68, 71 CB localization of hTR, dependent on, 146 epigenetic regulation of, 120 hTR–hTERT complex, 88 low methylation level, 119 mutations in human diseases, 70 peptide vaccine, 250, 251 positive cancer, 252 regulatory regions, 112 transcription, 97 (See also transcriptional regulation, of hTERT) Hutchinson–Gilford progeria, 255 hypoxia-induced signaling, 106 hypoxia response elements (HREs), 111 idiopathic pulmonary fibrosis (IPF), 9, 215, 255 IFD motif, 62, 70 Imetelstat (GRN163L), as telomerase inhibitor, 253, 254 immunotherapy, 250 induced pluripotent stem (iPS) cells, 224 insulin-like growth factor-1, 117 interferon a and g, 118 interferon stimulated gene 15 (ISG15), 246 interleukin-2 (IL-2), 118 JNK inhibitor SP600125, 121 Kluyveromyces lactis telomerase RNA, 37, 42 CGGA sequence motif in, 42 pseudoknot, 31, 32 Reg2, 41 template boundary elements (TBE), 28, 29 TWJ, critical for telomerase activity, 38 304 Ku70 and Ku80, 83, 96, 164, 219 long terminal repeats (LTRs), 286 major histocompatibility complex (MHC), 250 mammalian shelterin complex, 162 See also shelterin mammalian telomerase RNA assembly, 90 chaperone proteins, role of, 91–4 H/ACA binding proteins, role of, 90–1 post-translational regulation, 145–6 processing and stability, 82–3 mammalian telomeres See telomeres Mec1, 176 menin, 116, 117 mitochondrial genomes, 269 mitochondrial RNA processing endoribonuclease (RMRP), 10 mitogen-activated protein kinase (MEKK1)/ JNK pathway, 121 Moigliani (Moi), 163 Mre11, 166, 167, 169 Msh2, 217 Mtr10, 83 murine development, telomerase and telomere length in, 223–4 murine models, with abnormal shelterin function, 229–30 murine stem-cell function, in aging and immunity, 222-223 MYB domain, 161 myelodysplastic syndrome (MDS), Neurospora mitochondrial retroplasmids, 270 NF-kB signaling, 225, 230–1 NHP2 and NOP10, 145 nitroreductase in gene therapy, 252 NK cells, 118 non-Drosophilid insects, telomere maintenance in, 275–6 non-homologous end-joining (NHEJ), 164, 283, 289 non-LTR retrotransposons, 271, 279, 290 Gil(1/4Genie) in Giardia Lamblia, 279–80 in RNA-mediated DNA repair, 283 INDEX L1, 281–3 SART/TRAS in Bombyx Mori, 277–9 Zepp in Chlorella Vulgaris, 280–1 NO pathway, 118 NTPase, 40 nuclear hormone receptors, 111–13 nuclear reprogramming, telomerase and telomeres in, 224 nucleolar acetyltransferase NAT10, 93 nucleolar GTPase GNL3L, 93 nucleosome histones, modification of, 119 Okazaki fragment, 168, 225 oligonucleotide telomerase inhibitors, 253 stem cells, 255–6 telomere directed therapeutics, 254–5 oncoproteins, regulating hTERT transcription cellular, 113–14 viral, 114–15 Penelope-like elements (PLEs), 281-282 Phaeodactylum tricornutum PLE, 281 Philodina roseola PLE, 281 phosphoinositide 3-kinase (PI3K), 115 role in cell survival, 118 phytohaemagglutinin (PHA), 117 Pif1, 144 PI3K/Akt signaling pathway, 117 PinX1, 90 plant telomeres, 158 Pms2, 217 polymerase-independent activities, 205–6 polymorphonuclear neutrophils (PMN), 121 pontin, 93 Pot1a/Pot1b deficiency, 228, 229 POT gene, 178 POT1, 162 Pot proteins, 163 POT1–TPP1 complex, 177, 178 Poz1–Tpz1–Pot1–Ccq1 complex, 178 p38 pathway, 118 p53, 217 deficiency, development of lymphoma, 219 inducing endoreplication, 228 in hTERT repression, 115 premature aging syndromes, 219–20 prokaryote-to-eukaryote transition, 265 prokaryotic linear replicons, 269 INDEX prostate cancer, 106 protelomerases, 268 pseudoknot in TER, 30–4 ciliate, 30 structures, 28, 32 triple helix function, 33–4 vertebrate, 30–1 yeast, 31–3 p65–TER–TERT assembly, 95 305 RNA-dependent RNA polymerases, 10, 205, 207, 288 bacteriophages, 289 picorna-like viruses, 288 RNA–DNA duplex, 56, 61, 62, 64, 67, 69 RNA-mediated DNA repair, 283 RNA processing endoribonuclease (RMRP), 10, 204 RNA recognition motif (RRM), 35 RT–RH domain fusion, 288 QFP motif, 60 Rap1 proteins, 164, 171, 174, 214, 226 function in telomere-length regulation, 141, 161 human Rap1, 161 in higher eukaryotes, 174 mammalian, 230 modulate NF-kB signaling, 231 regulating subtelomeric silencing, 230–1 in shelterin, 227 to suppress fusions of telomeres in yeast, 164 for telomerase activation at telomeres, 144 Ras pathways, 118 repeat addition processivity (RAP), of telomerase, 2, 31, 36, 54, 67–9 replicometer, 244 reptin, 93 restriction enzyme-like (REL) endonuclease (EN) domain, 272 retinoblastoma- (Rb-) defective tumor cells, 253 retrotransposons, 11, 44, 54, 266, 270-275, 280, 285, 290 reverse transcriptase (RT), 53, 265, 267 See also telomerase reverse transcriptase CRISPR-associated, 290 Dualen, 287 pFOX retroplasmid, 270 phylogenetic relationships, 286-289 prokaryotic, 283-285 sequences in prokaryotic genomes, 266 uncharacterized, 284 ribonucleoprotein (RNP) complex, 23, 37, 43, 59, 72 ribosomal RNA (rRNAs), 82 Rif1 and Rif2, 161, 171, 173 RMRP See RNA processing endoribonuclease (RMRP) Saccharomyces cerevisiae, 80, 136, 158, 276 CDK activity, 181 telomeres length homeostasis, 180 telomerase holoenzyme in, 137–8 telomere length regulation, 141 telomeric DNA structures, 158 telomeric proteins in, 161–2 Sae2/Sgs1 pathway, 169 Schizosaccharomyces pombe, 80, 137 Dna2, function during lagging-strand replication, 168 POT1 conserved in, 227 RNA-directed RNA polymerase complex, 205 shelterin-like complex in, 162, 178 Taz1, 226 telomerase regulation in, 143–4 TER containing Sm site, 27 Tpz1 protein, role of, 69 senescence-associated secretory phenotype (SASP), 246 serine/threonine kinase receptors, 116 shelterin, 6, 11, 173, 178 components, 147, 162 mammalian, 224–5 to modulate telomerase activity, 183 murine models with abnormal shelterin, 229–30 recruitment of telomerase to telomeres, 147–8, 230 regulating telomere replication, 225-6 restraining recombination, 227–8 shelterin-like complex, in yeast, 162 shields ends from ATM and/or ATR-dependent DNA damage response, 226–7 in telomerase recruitment, 230 306 single-stranded telomere overhang, 166 mechanisms of formation, 168–70 small Cajal body RNAs (scaRNAs), 27 small nuclearRNAs (snRNAs), 27, 60, 66, 82 small nucleolar RNAs (snoRNAs), 27 snRNP assembly, in metazoans, 84 processing, stem-cell senescence, role of, 255 stem–H box–stem–ACA box structure, 82 Stn1 and Ten1, 142 Streptomyces anulatus, source of telomestatin, 255 survival of motor neuron (SMN), 93 SV40 large T antigen, 248 target-primed/extrachromosomally primed (TP/EP), priming mechanism, 286 target-primed reverse transcription (TPRT), 289-291 TATA box, 111, 121 Taz1, 161, 164, 226 TCAB1, 40 Tel1, 176 telomerase-associated proteins, 5, 79, 90 regulation of telomerase by, 172 p75, p65, p45, p43, and p20 in Tetrahymena, 94–6 telomerase-based anticancer therapies advantages and disadvantages, 251 small molecules for, 253 telomerase biogenesis, 83, 85, 87 telomerase complex beyond minimal components, 4–6 beyond telomere synthesis, 9–10 core components, 3-4, 44 discovery, 1–3, 12 regulation by telomeric proteins, and RNAs, 6–7 telomerase essential N-terminal (TEN) domain, 54 telomerase holoenzyme, 5, 8, 64, 79, 83–7, 90, 94–6, 138, 139, 141, 145, 175, 206 telomerase reverse transcriptase (TERT), 28, 53–4, 149, 213, 214, 265, 267 atomic resolution structures, 54 Bombyx TERT, 278 discovery, 53 domain organization and structures, 54–9 INDEX domain rearrangements upon nucleic acid binding, 65–6 GQ motif, 278 interaction with nucleic acid and nucleotide, 61–6 binding to telomeric DNA, 63 binding to template region of RNA, 61–2 interactions with nucleotide, 63–4 similarities to HIV-1 RT, 64–5 repeat addition processivity, 67–9 RT, similarity to, 267 structural organization, 278 TEN domain, 54, 58–9 telomerase RNA binding domain (TRBD), 54–5, 54–6, 59, 66–8, 71 Tribolium castaneum TERT mutants, modeled on, 70 with RNA–DNA hairpin, 61, 62 structure, 55, 58, 70 TEN domain missing from, 68 T-pocket, 60 telomerase RNA (TER), 3, 25, 79, 214 assembly/activation stem-loop, 34, 35 ciliate stem-loop IV, 35–7 vertebrate CR4–CR5 domain, 37 yeast three-way junction, 37–9 computational approach for TER identification, 26 core-enclosing helix, 29, 34 for Est2 binding, 33 for telomerase function in vivo, 34 disruption in Pot1b-deficient, 229 Kluyveromyces lactis telomerase RNA, 37, 42 CGGA sequence motif in, 42 pseudoknot, 31, 32 Reg2, 41 template boundary elements (TBE), 28, 29 TWJ, critical for telomerase activity, 38 Ku80-binding stem-loop, 41 processing and stability, 80-1 pseudoknot in TER, 30–4 ciliate, 30 structures, 28, 32 triple helix function, 33–4 vertebrate, 30–1 yeast, 31–3 INDEX telomerase accessory/regulatory proteins, binding sites for, 39–43 template boundary elements (TBEs), 28, 29, 59 template recognition element, 29 trafficking, 83–6 unusual diversity, 24–7 size, sequence, and secondary structure, 24–6 transcription and biogenesis, 26–7 telomerase RNA mutations, in human diseases, 43 telomerase RNP assembly, 59–61 TRBD domain role in, 59–60 TRBD–TER association, and template utilization, 60–1 telomerase vaccine, 250 telomere associations (TAs) in NHEJcompetent cells, 246 telomere-dysfunction induced foci (TIF), 213, 214 telomere length regulation, 136 altered dosage of TERT and TERC, consequence of, 220–2 negative feedback protein counting model, 136 proteins and interactions implicated in, 141 Rap1 function in, 161 telomere length, shortening of, 4, 7, 8, 43 affecting function of stem and progenitor cells, 216–18 and ATR-dependent DNA damage, 229 in cancer cells and, 250 caused by incomplete DNA replication, 43 contribute to stem cell dysfunction with age, 222, 255 deletion of either YKU70/YKU80 genes lead to, 164 elimination of POT genes in Arabidopsis and, 178 and human genetic disorders, 215 mutations in NBS1/ATM genes, 166 overexpression of TRF1, 148, 161 oxidative damage contribute to, 245 telomeres association of telomerase with, 138 Yku–TLC1 pathway of maintenance, 139 bacterial, types of, 267–9 307 bdelloid telomeres, 281 and cancer, 248 gene therapy, 252–3 immunotherapy, 250–1 telomerase chemotherapy approaches, 249–50 and cellular senescence, 244–8 Chlorella telomeres, 280 conservation of function, 1–3 damage, and p53 deficiency, 228 directed therapeutics, 254–5 Drosophila melanogaster telomeres, 274 dysfunction, 214, 217–20 in human tumor cells, 248 hypothesis of cellular aging and, length in murine development, 223–4 length maintenance, and genome stability, 216, 220–1, 248 TERT and TERC in, 216 in non-drosophilid insects and in arthropods, 275 maintenance without telomerase, 10–12 mammalian telomeres, 162, 254 in murine stem-cell function, in aging and immunity, 222–3 non-LTR retrotransposons, 272 in nuclear reprogramming, 224 plant telomeres, 158 prokaryotic telomeres, diversity of, 268 replication of, 159–61 generation of chromosome end structure, 160 replicative senescence (M1) and crisis (M2), 247 shelterin (See shelterin proteins) shortening (See telomere length, shortening of) single-stranded, 166 structure and function, 157–8, 213 telomerase-mediated and retrotransposonmediated, 267 in yeast, 276–7 telomere–telomere fusions, 254 telomeric DNA, 158, 244, 254 telomeric loop (t-loop), 158, 244, 269 telomeric repeat containing RNA (TERRA), 7, 149–50, 224 template boundary element (TBE), in TER, 29, 29, 59 308 template recognition element (TRE), in TER, 29 TEN domain, 58–9 TERC See telomerase RNA terminal inverted repeats (TIRs), 268 terminal proteins (TP), 268 terminal transferase, 205 terminin, 2, 163 TERT See telomerase reverse transcriptase TER–TERT complex, 79 TERT–RMRP complex, 204, 205 Tetrahymena thermophila, 1, 91–2, 167 G-tails of defined length, 167 structure of TRBD, 56 TBE in TER, 66 telomerase activity, 23 telomerase holoenzyme biogenesis, 94–6 telomerase RNAs, disruption of, pseudoknot structures, 32 secondary structure models, 25 Thermosynechococcus elongates Group II intron, 284 three-way junction (TWJ), in TER, 38–9 TIF See telomere-dysfunction induced foci (TIF) TIN2, 173 T lymphocytes, 250 T-pocket, in TRBD, 60 transcriptional regulation, of hTERT, 105, 108, 120–1 by cellular and viral oncoproteins, 113–17 factors involved in regulation, 109–10 by growth factors and cytokines, 117–19 nonhormonal transcription factors, 108, 111 nuclear hormone receptors, 111–13 by tumor suppressors, 115–17 transcription factors (TRs), 108 INDEX transforming growth factor b, 116 translocation, step in telomerase reaction, 69 TRAP assay, 249 TRBD See telomerase RNA binding domain (TRBD) TRF-like proteins, 163 TRF proteins, 161, 162, 173 Tribolium castaneum telomere, 275 Tribolium castaneum TERT mutants, modeled on, 70 with RNA–DNA hairpin, 61, 62 structure, 55, 58, 70 TEN domain missing from, 68 triple helix model, of TER pseudoknot, 33–4 tumorigenesis, 8, 105, 107, 108, 115, 116, 218, 219, 247 tumor suppression mechanism, 256 tumor suppressors, 115, 249 regulating hTERT transcription, 115–17 Ty5-encoded integrase (IN), 277 tyrosine recombinase, 268, 288 unstable angina (UA), 121 Verrocchio (Ver), 163 viral oncoproteins, 113 regulating hTERT transcription, 114–15 viral RNA polymerases, 56 Watson–Crick base pairing, 64 WDR79, 40 Werner syndrome, 215, 219 Wilms’ tumor protein, 116 wortmanin, 117 xenograft models, 252, 253, 257 Y-family DNA polymerases, 65 YKu–TLC1 interaction, 96, 139, 175 YKU70/YKU80, 164 ... TELOMERASES Chemistry, Biology, and Clinical Applications Edited by NEAL F LUE Weill Medical College of Cornell University, New York, NY, USA CHANTAL AUTEXIER Departments of Anatomy and Cell Biology, and. .. template recognition element (TRE), and template boundary element (TBE) Telomerases: Chemistry, Biology, and Clinical Applications, First Edition Edited by Neal F Lue and Chantal Autexier Ó 2012 John... chapter) (Cesare and Reddel, 2010; Jain et al., 2010) Recombination can occur Telomerases: Chemistry, Biology, and Clinical Applications, First Edition Edited by Neal F Lue and 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