Isbn 0321223603

Cold Spring Harbor Laboratory Press

Publisher and Sponsoring Editor: John Iriglis Editorial Director: Alexander Gann Editorial Development Manager: Jan Argentin?. Project Manager and Developmental Editor:

Kaaren Janssen Project Coordinator: Maryliz Dickerson Editorial Development Assistant: Nora Rice Crystal structure images: Leemor Joshua-Tor Cover concept sketch: Erica Beade, MBC Graphics

Cover Designers: Denise Weiss, Ed Atkeson

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Preface s the fifth edition of Molecular Biology of the Gene goes to press, completion of the human genome sequence is no longer news. This whs not something that could safely have been anticipated when the first edition appeared in 1965; even when the Fourth edition came out in ii)fl7, Few if any foresaw how quir.kly we would move into a world where whole genomes, not just individual genes, could be visualized and compared. There has been a comparable leap in the elucidation of protein structures as well. Thus, in the last few years, the structures of the huge molecular machines thai drive the basic processes discussed in this book—DNA transcription, replication, protein synthesis, and so forth—have largely been solved at the atomic level, and many details of their inner workings revealed.

Thu new edition of Mofccular Biology of the Gone reflects these advances, and many others besides. Gut when we sat down to plan this latest version, wc were all of a mind that much of the organization and scope of the original book should be retained. This was not a matter of convenience—inevitably, in light of the dramatic changes that had taken place since the last edition, the vast bulk of the text had to be completely rewritten anyway, and all the art rendered afresh. No, the reasoning was simply that, more than ever in this genomic era, there seemed a need for a book that explained what genes Hit; aiid how diey work, and this was exactly what Molecular Biology of the Gene had originally been designed to do.

Thus, we have resisted the temptation to become encyclopedic or to delve info allied disciplines, such as cell biology. Also, we wanted the new edition to retain u focus on principles and concepts, another feature of its predecessors. And so we illustrate our discussion sparingly with experiments, which appear mainly in boxes. These considerations ensured the book did not become unwieldy. As stated by its author in the preface to the first edition: "Often I present a fact, and, because of lack of space, f cannot outline the experiments that demonstrate its validity. Given the choice between deleting an important principle or giving an experimental detail, 1 am inclined to state the principle." The current incarnation of Molecular Biology of the Gene adheres unapologeticalty to this philosophy.

An outline of this new edition will thus be familiar to anyone who has used the book before. We begin (in Part t) with a series of chapters [modified in the current edition) that place the field of molecular biology in context. These chapters summarize the history of genetics and molecular biology and also present the timeless chemical principles that determine the structure and function of macromolecules. The text thereafter is organized to follow a familiar flow of topics. The nature of the genetic material, its organization and its maintenance, are discussed in Part 2; in addition to chapters on DlSiA structure, replication, recombination, and repair, new to this part of the book is a chapter od. chromosomes, chromatin, and the liucleosome. This addition reflects current appreciation of how the context in which a given gene is found intluences its Function and regulation.

The passage of information from gene to protein-—so-called gene expression — is covered in Part 3; and in Part 4 we describe the regulation of that process. As well as chapters on thn basic mechanisms of gene regulation, Part 4 has chapters on the regulation of gene expression in animal development and in the evolution of animal diversity. These chapters again conform to a tradition established by earlier editions: always (here has been a chapter or two linking basic mechanisms of molecular biology to pressing biological questions. In. the current edition, these chapters investigate perhaps the most striking revelation to come from comparing the complete genome sequences of various animals; different animals— including humans-—contain largely the same genes and so differences between those animals must result largely from changes in how those genes are expressed.

New to the current edition is the final pari — Part 5—comprising chapters on experimental methods—the techniques of molecular biology, genomics, and bioinformatics—and on the model organisms whose study iias revealed many of the underlying principJes of molecular biology.

We alluded to the explosion in the numbers of atomic structures solved in the last few years. These include not only many of the enzymes that mediate the basic processes of molecular biology, and many of the proteins that regulate those processes, but the nucleo-some as well. While it remains true that many of the basic concepts in molecular biology can be understood without reliance on structural detail—indeed it is one of the strengths of the field that this is the case—nevertheless, many mechanistic insights come only from seeing these details. Accordingly, where structures shed light on how the molecules in question work, wc present them; and we do so in a consistent style throughout the book.

Kach part opener includes a short text, outlining what will be covered in the coming chapters, and a few photographs. These pictures, from the Cold Spring Harbor Laboratory Archive, were all taken at the Laboratory on Long Island, the great majority at the Symposium hosted there almost every summer since 1933. Captions identify who is in each picture and when it was taken. We thank Clare Bunce and the CSHL Archive for help with these.

Parts of the current edition grew out of an introductory course on molecular biology taught by one of us (RL) at Harvard University, and this author is grateful to Steve Harrison and Jim Wang who contributed to this course in past years and whose influence is reflected in Chapter 6 and elsewhere. We have shown sections of the manuscript to various colleagues and their comments have been most valuable, greatly improving the accuracy and accessibility of the text and figures, Specifically we thank: jamie Cate, Richard Ebright, Mike Essen, Cliris Fromme, Ira Hall, Adrian Krainer, Karolin Luger, Bill McGinnis, Matt Michael, Lily Mirels, Nipam Pate!, Craig Peterson, Mark Ptashne, Uttam RajBhandary, and Bruce Still man. In addition, Craig Hunter drafted the section on the Worm for Chapter 21. We also thank those who prov ided us with figures, or the wherewithal! to create them, including: Sean Carroll, Seth Darst, Edward Egelman, Georg Haider, Stuart Kim, Bil! McGinnis, Steve Paddock, Phoebe Rice, Matt Scott, Peter Sorger, Andrzej Stasiak, Tom Steitz, Dan Voytas, and Steve West.

We are most grateful to Leernor joshua-Tor who rendered all the structure figures, often producing multiple versions and patiently helping us see which best needed. We are also grateful to those who provided (.heir software1; Per Kraulis,. Robert Esnouf, Ethan Merritt, and Barry Ho nig. Coordinates were obtained from the Protein Data Bank (; and citations to those who solved each structure are included in the figure legends.

Our art program was developed and rendered by a talented and enthusiastic team from the Dragonfly Media Croup, led by Mike Demaray and Craig Durant Renate Helhniss helped to develop some of our initial sketches and provided early renderings of a number of figures. The cover image was rendered by Tomo Narashimu from an author concept sketch by Erica Beade {MBC Graphics).

We thank those at Cold Spring Harbor Laboratory Press who handled development of this book, /an Argentine, despite having to enforce the deadlines, was throughout less cajoling than she was tirelessly engaged in helping us solve the problems these presented. Maryliz Dickerson kept organized the mass nf material we generated and Nora Rice helped coordinate author meetings and other aspects of the project. Deniso Weiss and Ed Atkeson produced the cover design; and fohn Inglis, who initiated this collaboration, was on hand with advice at critical points in the process. Most of all. Kaaren fanssen, our editor, kept evervthing afloat with <jii energy, enthusiasm, and activity far beyond anything we could reason* ably have asked for; things simply would not have got to this point without her.

We also wish to acknowledge the work of those at Benjamin Curn-minga who coordinated production of the book. Prank Ruggireifo oversaw the process carried out by Jim Smith, Kay Ueno. Corinne Benson, Alexandra Fell owes, Jeanne Zalnsky, and Donna KalaL Ingrid Mount at Kim Street Publishing Services coped cheerfully with the many rounds of changes to art and text even very late in the process. Michele Sordi, while part of the Benjamin Cummings team, helped bring us all together in the first place.

And finally we gratefully acknowledge our families and friends who, throughout this period, provided such strong support, despite having to put up with our frequent absences and distractions.

James D, Watson Tania A. Baker Stephen P. Bell Alexander tiann Michael Levine Richard Losick

! Per Kraulis granted permission to use MolScripl (Kratili* P J 1991. MOLSCKtPT: A program to produce both detailed and schematic: pints of protein structures. Journal of Applied Crystallography 24- 946-950). Robert Esnouf gave permission tu use Bab Script (Esnouf R.M, 190? journal of Molecular Graphics 15: 132 134) In addition. Ethan Merritt gave us use ui Knsl«3D (Merritl E.A. and Bacon Lt.J. 1997 RttSlfr3D: Photorealistic Molecular Graphic«. Methods in Enzymolngy 277: S05 524), ond Rirry l ionig granted permission to use GRASP (Nicolls A., Sharp K.A r art! Honig B. 1991. Protein folding arid association- insights from tile interfatiaJ and thermodynamic properties uT hydrocarbons. Pro!dins 11: 281 -296).

About the Authors

JAMES D. WATSON was Director of Cold Spring Harbor laboratory from 1968 to 1993 and is now its President. He spent his undergraduate years at the University of Chicago and received bis Ph.D. in 1950 from Indiana University. Between 1950 and 1953, he did postdoctoral research in Copenhagen and (Cambridge, England, While at Cambridge, he began the collaboration that resulted in the elucidation of the double-helical structure of DNA in 1953. (For this discovery, Watson, Francis Crick, and Maurice Wilkins were awarded the Nobel Prize in 1962.) Later in 1953, he went to the California Institute of Technology. He moved to Harvard in 1955, where he taught and did research on RNA synthesis and protein synthesis until 1976. He was the fust Director of the National Center for Genome Research of the National institutes of Health from 1989 to 1992. Dr. Watson was solti author of the first, second, and third editions of Mo lecular Biology of the Gene, anil a co-author of (he fourth edition. These were published in 1965, 1970, 1976, and 1987 respectively. Watson has also been involved in two other textbooks: he was one of the original authors of Molecular Biology of the Cell, and is also an author of Recombinant DNA: a Short Course.

TAMA A. BAKER is the Whitehead Professor of Biology at the Massachusetts Institute of Technology and an Investigator of the Howard Hughes Medical Institute. She received a B.S. in biochemistry from the University of Wisconsin, Madison, and a Ph.D, in biochemistry from Stanford University in 1988. Her graduate research was carried out in the laboratory of Professor Arthur Kornberg and focused on mechanisms of initiation of DNA replication. She did postdoctoral research in the laboratory uf Dr. Kiyoshi Mizuuchi at the National Institutes of Health, studying Uie mechanism and regulation of DNA transposition. Her current research explores mechanisms and regulation of genetic recombination, enzyme-catalyzed protein unfolding, and ATP-dependent protein degradation. Professor Baker received the 2001 Eli Lilly Research Award from the American Society of Microbiology and the 2000 MIT School of Science Teaching Prize for Undergraduate Education. She is co-author (with Arthur Knrnberg) of the book DAM Replication, Second Edition.

STEPHEN P. BELL is a Professor of Biology at the Massachusetts Institute of Technology and an Assistant Investigator of the Howard Hughes Medical Institute. He received B.A. degrees from the Department of Biochemistry, Molecular Biology, and Cell Biology and the Integrated Sciences Program at Northwestern University and a Ph.D. in biochemistry at the University of California, Berkeley in 1991, His graduate research was carried out in the laboratory of Dr. Robert Tjian and focused on eukaryotic transcription. He did postdoctoral research in the laboratory of Dr. Bruce Stilljnan at Cold Spring Harbor laboratory, working on the initiation of eukaryotic DNA replication. His current research focuses on the mechanisms controlling the duplication of eukaryotic chromosomes. Professor Bell received the 2001 ASBMB-Schering Plough Scientific Achievement Award and the Everett Moore Baker Memorial Award for Excellence in Undergraduate Teaching at MIT In 1998.

ALEXANDER GANN is Editorial Director of Cold Spring Harbor Laboratory Press, and a faculty member of the Watso« School of Bio* logical Sciences at Cold Spring Harbor Laboratory. He received his B.St: in microbiology from University College London and a Ph.D. tn molecular biology from The University of Edinburgh in 1989. His graduate research was carried out in ihe laboratory of Noreen Murray and focused on DNA recognition by restriction enzymes. He did postdoctoral research in the laboratory of Mark Ptiishne ai Harvard, working on transcriptional regulation, and that of Jeremy Brockes at the Ludwig Institute of Cancer Research at University College London, where he worked on newt limb regeneration. He was a Lecturer at Lancaster University, England, from 1996 to 1999, before moving to Cold Spring Harbor Laboratory. He is co-author (with Mark Ptashne) of the book Geties & Signals (2002).

MICHAEL LEVINE is a Professor of Molecular and Cell Biology at the University of California, Berkeley, and in also Co-Director of the Center for Integrative Genomics. He received his B.A. from the Department of Genetics at the University of California, Berkeley, and his Ph,D. with Alan Gaien in the Department of Molecular Biophysics and Biochemistry from Yale University in 1981. As a postdoctoral fellow with Walter Gahring and Gerry Rubin from 1382-1984, he studied the molecular genetics of Drosophih development. Professor Levine's research gTOup currently studies the gene networks responsible for the gastnilation of the DrosophiJa and Ciono (sea squirt) embryos. He holds the P. Williams Chair in Genetics and Development at the University of California, Berkeley. He was awarded the Monsanto Prize in Molecular Biology from the National Academy of Sciences in 1996, and was elected to the Amtsrican Academy of Arts and Sciences in 1998 and the National Academy of Sciences in 1998.

RICHARD M. LOSICK is the Maria Moors Cabot Professor of Biology, a Harvard College Professor, and a Howard Hughes Medical Institute Professor in the Faculty of Arts & Sciences at Harvard University. He received his A.B. in chemistry at Princeton University and his Ph.D. in biochemistry at the Massachusetts Institute of Technology. Upon completion of his graduate work. Professor Losick was named a Junior Fellow of the Harvard Society of f ellows when he began his studies on RNA polymerase and the regulation of gene transcription in bacteria. Professor Losick is a past Chairman of the Departments of Cellular and Developmental Biology and Molecular and Cellular Biology at Harvard University. He received the Camille and Henry Dreyfuss Teacher-Scholar Award, is a member of the National Academy of Sciences, a Fellow of the American Academy of Arts and Sciences, a Fellow of the American Association for the Advancement of Science, a Fellow of the American Academy of Microbiology, and a former Visiting Scholar of the Phi Beta Kappa Society.

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