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Summary of Molecular Biology of the Gene

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MOLECULARBIOLOGYOFTHE GENES E V E N T H E D I T I O NJAMES D. WATSON ALEXANDER GANNCold Spring Harbor Laboratory Cold Spring Harbor LaboratoryTANIA A. BAKER MICHAEL LEVINEMassachusetts Institute of Technology University of California, BerkeleySTEPHEN P. BELL RICHARD LOSICKMassachusetts Institute of Technology Harvard UniversityWithSTEPHEN C. HARRISONHarvard Medical School(Chapter 6: The Structure of Proteins)Boston Columbus Indianapolis New York San Francisco Upper Saddle RiverAmsterdam Cape Town Dubai London Madrid Milan Munich Paris Montre´al TorontoDelhi Mexico City Sa˜o Paulo Sydney Hong Kong Seoul Singapore Taipei TokyoCOLD SPRING HARBOR LABORATORY PRESSCold Spring Harbor, New York

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PEARSON COLD SPRING HARBOR LABORATORY PRESSEditor-in-Chief: Beth Wilbur Publisher and Sponsoring Editor: John InglisSenior Acquisitions Editor: Josh Frost Editorial Director: Alexander GannExecutive Director of Development: Deborah Gale Director of Editorial Development: Jan ArgentineAssistant Editor: Katherine Harrison-Adcock Managing Editor and Developmental Editor: Kaaren JanssenManaging Editor: Michael Early Project Manager: Inez SialianoProduction Project Manager: Lori Newman Production Manager: Denise WeissIllustrators: Dragonfly Media Group Production Editor: Kathleen BubbeoManufacturing Buyer: Michael Penne Permissions Coordinator: Carol BrownDirector of Marketing: Christy Lesko Crystal Structure Images: Leemor Joshua-Tor and Stephen C. HarrisonExecutive Marketing Manager: Lauren Harp Cover Designer: Mike AlbanoExecutive Media Producer: Laura TommasiEditorial Media Producer: Lee Ann DoctorSupervising Media Project Manager: David ChavezDirector of Content Development, MasteringBiology: Natania MlawerContent Specialist, MasteringBiology: J. Zane Barlow, PhDFront and Back Cover Images: Far left, drawing by Francis Crick, Wellcome Library, London. Second from left, fromWatson J.D.andCrickF.H.C. 1953.Nature171: 737–738. Second fromright, IrvingGeis illustration.Rights ownedbyHowardHughesMedicalInstitute. Not to be reproduced without permission. Far right, structure by Leemor Joshua-Tor (image prepared with PyMOL).Credits and acknowledgments for materials borrowed from other sources and reproduced, with permission,in this textbook appear on the appropriate page within the text.Copyright # 2014, 2008, 2004 Pearson Education, Inc. All rights reserved. Manufactured in the United States of America. Thispublication is protected by Copyright, and permission should be obtained from the publisher prior to any prohibited reproduc-tion, storage in a retrieval system, or transmission in any form or by anymeans, electronic, mechanical, photocopying, recording,or likewise. To obtain permission(s) to use material from this work, please submit a written request to Pearson Education, Inc.,Permissions Department, 1900 E. Lake Ave., Glenview, IL 60025. For information regarding permissions, call (847) 486-2635.Readersmay view, browse, and/or downloadmaterial for temporary copying purposes only, provided these uses are for noncom-mercial personal purposes. Except as provided by law, this material may not be further reproduced, distributed, transmitted,modified, adapted, performed, displayed, published, or sold in whole or in part, without prior written permission from thepublisher.Manyof the designations used bymanufacturers and sellers to distinguish their products are claimed as trademarks.Where thosedesignations appear in this book, and the publisher was aware of a trademark claim, the designations have been printed in initialcaps or all caps.MasteringBiology and BioFlix are trademarks, in the U.S. and/or other countries, of Pearson Education, Inc. or its affiliates.Library of Congress Cataloging-in-Publication DataWatson, James D.Molecular biology of the gene / James D. Watson, Cold Spring Harbor Laboratory, Tania A. Baker, Massachusetts Institute of Technology,Alexander Gann, Cold Spring Harbor Laboratory, Michael Levine, University of California, Berkeley, Richard Losick, Harvard University.pages cmIncludes bibliographical references and index.ISBN-13: 978-0-321-76243-6 (hardcover (student ed))ISBN-10: 0-321-76243-6 (hardcover (student ed))ISBN-13: 978-0-321-90537-6 (paper (a la carte))ISBN-10: 0-321-90537-7 (paper (a la carte))[etc.]1. Molecular biology--Textbooks. 2. Molecular genetics--Textbooks. I. Title.QH506.M6627 2013572’.33--dc2320120460931 2 3 4 5 6 7 8 9 10—DOW—17 16 15 14 13ISBN 10: 0-321-76243-6 (Student Edition)ISBN 13: 978-0-321-76243-6 (Student Edition)www.pearsonhighered.comISBN 10: 0-321-90264-5 (Instructor’s Review Copy)COLD SPRING HARBOR ISBN 13: 978-0-321-90264-1 (Instructor’s Review Copy)LABORATORY PRESSISBN 10: 0-321-90537-7 (Books a` la Carte Edition) ISBN 13: 978-0-321-90537-6 (Books a` la Carte Edition)

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PrefaceHENEW EDITION OF MOLECULAR BIOLOGYOF THE GENE appears in this, its 7th edition, onthe 60th anniversary of the discovery of the structure of DNA in 1953, an occasionTcelebrated by our cover design. The double-helical structure, held together by spe-cific pairing between the bases on the two strands, has become one of the iconic imagesof science. The image of the microscope was perhaps the icon of science in the late19th century, displaced by the mid 20th century by the graphical representation of theatomwith its orbiting electrons. But by the end of the century that image had in turn givenway to the double helix.The field of molecular biology as we understand it today was born out of the discoveryof theDNAstructure and the agenda for research that that structure immediately provided.The paper byWatson andCrick proposing the double helix endedwith a now famous sen-tence: “It has not escaped our notice that the specific pairing we have postulated immedi-ately suggests a possible copying mechanism for the genetic material.” The structuresuggested how DNA could replicate, opening the way to investigate, in molecular terms,how genes are passed down through generations. It was also immediately apparent thatthe orderof bases along aDNAmolecule could represent a “genetic code,” and so an attackon that second great mystery of genetics—how genes encode characteristics—could alsobe launched.By the time the first edition of Molecular Biology of the Gene was published, just 12years later in 1965, it had been confirmed that DNA replicated in the manner suggestedby the model, the genetic code had all but been cracked, and the mechanism by whichgenes are expressed, and how that expression is regulated, had been established at leastin outline. The field of molecular biology was ripe for its first textbook, defining for thefirst time the curriculum for undergraduate courses in this topic.Our understanding of the mechanisms underlying these processes has hugelyincreased over the last 48 years since that first edition, often driven by technologicaladvances, including DNA sequencing (another anniversary this year is the 10th anniver-sary of completion of the human genome project). The current edition of Molecular Biol-ogy of the Gene celebrates both the central intellectual framework of the field put in placein that first edition and the extraordinary mechanistic, biological, and evolutionaryunderstanding that has since been achieved.New to This EditionThere are a number ofmajor changes to the newedition. Aswell as wide-ranging updates,these include changes in organization, addition of completely newchapters, and the addi-tion of new topics within existing chapters.. New Part 2 on the Structure and Study of Macromolecules. In this new section, each of thethreemajormacromolecules gets its ownchapter. TheDNAchapter is retained from theprevious edition, but what was previously just a short section at the end of that chapteris now expanded into a whole new chapter on the structure of RNA. The chapter onthe structure of proteins is completely new andwas written for this edition by StephenHarrison (Harvard University).v

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vi Preface. Techniques chapter moved from the end of the book into Part 2. This revised and relocatedchapter introduces the important techniques that will be referred to throughout thebook. In addition to many of the basic techniques of molecular biology, this chapternow includes an updated section on many genomics techniques routinely employedby molecular biologists. Techniques more specialized for particular chapters appearas boxes within those chapters.. Completely new chapter on The Origin and Early Evolution of Life. This chapter shows howthe techniques of molecular biology and biochemistry allow us to consider—evenreconstruct—how life might have arisen and addresses the prospect of creating lifein a test tube (synthetic biology). The chapter also reveals how, even at the very earlystages of life, molecular processes were subject to evolution.. Newmaterial onmany aspects of gene regulation. Part 5 of the book is concernedwith generegulation. In this edition we have introduced significant new topics, such as quorumsensing in bacterial populations, the bacterial CRISPR defense system and piRNAs inanimals, the function of Polycomb, and increased discussion of other so-called “epige-netic” mechanisms of gene regulation in higher eukaryotes. The regulation of “pausedpolymerase” atmany genes during animal development and the critical involvement ofnucleosome positioning and remodeling at promoters during gene activation are alsonew topics to this edition.. End-of-chapter questions. Appearing for the first time in this edition, these include bothshort answer anddata analysis questions. The answers to the even-numbered questionsare included as Appendix 2 at the back of the book.. New experiments and experimental approaches reflecting recent advances in research. Inte-grated within the text are new experimental approaches and applications that broadenthe horizons of research. These include, for example, a description of how the geneticcode can be experimentally expanded to generate novel proteins, creation of a syntheticgenome to identify the minimal features required for life, discussion of new genome-wide analysis of nucleosome positioning, experiments on bimodal switches in bacte-ria, and hownewantibacterial drugs are being designed that target the quorum-sensingpathways required for pathogenesis.SupplementsMasteringBiology www.masteringbiology.comMasteringBiology is an online homework, tutorial, and assessment system that deliversself-paced tutorials that provide individualized coaching, focus onyourcourse objectives,and are responsive to each student’s progress. The Mastering system helps instructorsmaximize class timewith customizable, easy-to-assign, and automatically graded assess-ments thatmotivate students to learn outside of class and arrive prepared for lecture.Mas-teringBiology includes the book’s end-of-chapter problems, eighteen 3D structuretutorials, reading quizzes, animations, videos, and a wide variety of activities. The eTextis also available throughMasteringBiology, providing access to the complete textbook andfeaturing powerful interactive and customization functions.Instructor Resource DVD 978-0-321-88342-1/0-321-88342-XAvailable free to all adopters, this dual-platform DVD-ROM contains all art and tablesfrom the book in JPEG and PowerPoint in high-resolution (150 dpi) files. The PowerPointslides include problems formatted for use with Classroom Response Systems. This DVD-ROMalso contains an answer key for all of the end-of-chapter Critical Thinking questionsincluded in MasteringBiology.Transparency Acetates 978-0-321-88341-4/0-321-88341-1Features approximately 90 four-color illustrations from the text. These transparencies arefree to all adopters.

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Preface viiCold Spring Harbor Laboratory PhotographsAs in the previous edition, each part opener includes photographs, some newly added tothis edition. These pictures, selected from the archives of Cold Spring Harbor Laboratory,were all taken at the Lab, the greatmajority during the Symposia hosted there almost everysummer since 1933. Captions identifywho is in eachpicture andwhen itwas taken.Manymore examples of these historic photos can be found at the CSHL archiveswebsite ( of the current edition grewout of an introductory course onmolecular biology taughtby one of us (RL) at Harvard University, and this author is grateful to Steve Harrison andJimWangwhocontributed to this course in past years. In the case of SteveHarrison,we areadditionally indebted to him for writing and illustrating a brand new chapter on proteinstructure especially for this new edition. No one could be better qualified for such a task,andwe are the grateful beneficiaries of—and the book is immeasurably improved by—hiscontribution.We are also grateful to Craig Hunter, who earlier wrote the section on the worm forAppendix 1, and to Rob Martienssen, who wrote the section on plants for that sameappendix.We have shown sections of the manuscript to various colleagues and their commentshave been extremely helpful. Specifically we thank Katsura Asano, Stephen Blacklow,Jamie Cate, AmyCaudy, Irene Chen, Victoria D’Souza, Richard Ebright, Mike Eisen, ChrisFromme, Brenton Graveley, Chris Hammell, Steve Hahn, Oliver Hobert, AnnHochschild,Jim Hu, David Jerulzalmi, Leemor Joshua-Tor, Sandy Johnson, Andrew Knoll, AdrianKrainer, Julian Lewis, Sue Lovett, Karolin Luger, Kristen Lynch, Rob Martienssen, BillMcGinnis, Matt Michael, LilyMirels, Nipam Patel, Mark Ptashne, Danny Reinberg, Dimi-tar Sasselov, David Shechner, Sarah T. Stewart-Mukhopadhyay, Bruce Stillman, and JackSzostak.We also thank those who provided us with figures, or the wherewithal to create them:Sean Carroll, Seth Darst, Paul Fransz, Brenton Graveley, Ann Hochschild, Julian Lewis,Bill McGinnis, Phoebe Rice, Dan Rokhsar, Nori Satoh, Matt Scott, Ali Shilatifard, PeterSorger, Tom Steitz, Andrzej Stasiak, Dan Voytas, and Steve West.New to this edition are end-of-chapter questions, provided byMary EllenWiltrout, andwe thank her for these efforts that have enhanced the newedition. In addition,Mary Ellenhelped with revisions to the DNA repair chapter.We are indebted to Leemor Joshua-Tor, who so beautifully rendered themajority of thestructure figures throughout the book. Her skill and patience are much appreciated.1We are also grateful to those who provided their software : Per Kraulis, Robert Esnouf,Ethan Merritt, Barry Honig, and Warren Delano. Coordinates were obtained from theProtein Data Bank (, and citations to those who solved each structureare included in the figure legends.Our art programwas again executed by a team from the Dragonfly Media Group, led byCraigDurant. DeniseWeiss andMikeAlbanoproduced a beautiful cover design.We thankClare Bunce and the CSHL Archive for providing the photos for the part openers and formuch help tracking them down.We thank Josh Frost at Pearsonwho oversaw our efforts andwas always on hand to helpus out or provide advice. In development at CSHLPress, JanArgentine provided great sup-port, guidance, and perspective throughout the process. Our heartfelt thanks to KaarenJanssen who was once again our constant savior—editing and organizing, encouragingand understanding—and unstintingly good-humored even on the darkest days. InezSialiano kept track of the output, and Carol Brown dealt with the permissions as effi-ciently as ever. In production, we relied heavily on the extraordinary efforts and patience

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viii Prefaceof Kathleen Bubbeo, for which we are most grateful. And we must also thank DeniseWeiss, who oversaw production and ensured that the book looked so good by finessingthe page layout and creating the design. John Inglis as ever created the environment inwhich this could all take place.And once again, we thank our families for putting up with this book for a third time!JAMES D. WATSONTANIA A. BAKERSTEPHEN P. BELLALEXANDER GANNMICHAEL LEVINERICHARD LOSICK1Per Kraulis granted permission to use MolScript (Kraulis P.J. 1991. MOLSCRIPT: A program to produce bothdetailed and schematic plots of protein structures. J. Appl. Cryst. 24: 946–950). Robert Esnouf gave permissionto use BobScript (Esnouf R.M. 1997. J. Mol. Graph. 15: 132–134). In addition, Ethan Merritt gave us use ofRaster3D (Merritt E.A. and Bacon D.J. 1997. Raster3D: Photorealistic molecular graphics. Methods Enzymol.277: 505–524), and Barry Honig granted permission to use GRASP (Nicolls A., Sharp K.A., and Honig B.1991. Protein folding and association: Insights from the interfacial and thermodynamic properties of hydrocar-bons. Proteins 11: 281–296).WarrenDeLano agreed to the use of PyMOL (DeLanoW.L. 2002. The PyMOLMolec-ular Graphics System. DeLano Scientific, Palo Alto, California).

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About the AuthorsJAMES D. WATSON is Chancellor Emeritus at Cold Spring Harbor Laboratory, where hewas previously its Director from 1968 to 1993, President from 1994 to 2003, and Chancel-lor from 2003 to 2007. He spent his undergraduate years at the University of Chicago andreceived his Ph.D. in 1950 from Indiana University. Between 1950 and 1953, he did post-doctoral research in Copenhagen and Cambridge, England.While at Cambridge, he beganthe collaboration that resulted in the elucidation of the double-helical structure of DNA in1953. (For this discovery, Watson, Francis Crick, and Maurice Wilkins were awarded theNobel Prize in 1962.) Later in 1953, he went to the California Institute of Technology. Hemoved to Harvard in 1955, where he taught and did research on RNA synthesis and pro-tein synthesis until 1976. He was the first Director of the National Center for GenomeResearch of the National Institutes of Health from 1989 to 1992. Dr. Watson was soleauthor of the first, second, and third editions of Molecular Biology of the Gene, and aco-author of the fourth, fifth and sixth editions. These were published in 1965, 1970,1976, 1987, 2003, and 2007, respectively. He is also a co-author of two other textbooks,Molecular Biology of the Cell and Recombinant DNA, as well as author of the celebrated1968 memoir, The Double Helix, which in 2012 was listed by the Library of Congress asone of the 88 Books That Shaped America.TANIAA. BAKER is theHead of the Department andWhitehead Professor of Biology at theMassachusetts Institute of Technology and an Investigator of the HowardHughesMedicalInstitute. She received a B.S. in biochemistry from the University ofWisconsin, Madison,and a Ph.D. in biochemistry from Stanford University in 1988. Her graduate research wascarried out in the laboratory of Professor Arthur Kornberg and focused on mechanismsof initiation of DNA replication. She did postdoctoral research in the laboratory ofDr. Kiyoshi Mizuuchi at the National Institutes of Health, studying the mechanism andregulation of DNA transposition. Her current research explores mechanisms and regula-tion of genetic recombination, enzyme-catalyzed protein unfolding, and ATP-dependentprotein degradation. Professor Baker received the 2001 Eli Lilly Research Award from theAmerican Society ofMicrobiology and the 2000MIT School of Science Teaching Prize forUndergraduate Education and is a Fellow of the American Academy of Arts and Sciencessince 2004 andwas elected to theNational Academyof Sciences in 2007. She is co-author(with Arthur Kornberg) of the book DNA Replication, Second Edition.STEPHEN P. BELL is a Professor of Biology at the Massachusetts Institute of Technologyand an Investigator of the Howard Hughes Medical Institute. He received B.A. degreesfrom the Department of Biochemistry, Molecular Biology, and Cell Biology and the Inte-grated Sciences Program at Northwestern University and a Ph.D. in biochemistry at theUniversity of California, Berkeley, in 1991. His graduate research was carried out in thelaboratory of Dr. Robert Tjian and focused on eukaryotic transcription. He did postdoc-toral research in the laboratory of Dr. Bruce Stillman at Cold Spring Harbor Laboratory,working on the initiation of eukaryotic DNA replication. His current research focuseson the mechanisms controlling the duplication of eukaryotic chromosomes. ProfessorBell received the 2001 ASBMB–Schering Plough Scientific Achievement Award, theix


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