Cold Spring Harbor Symposia on Quantitative Biology

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COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY

VOLUME LVIII COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY

VOLUME LVIII

DNA and Chromosomes

COLD SPRING HARBOR LABORATORY PRESS 1993 COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY VOLUME LVIII 1993 by The Cold Spring Harbor Laboratory Press International Standard Book Number 0-87969-065-8 (cloth) International Standard Book Number 0-87969-066-6 (paper) International Standard Serial Number 0091-7451 Library of Congress Catalog Card Number 34-8174

COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY

Founded in 1933 by REGINALD G. HARRIS Director of the Biological Laboratory 1924 to 1936

Previous Symposia Volumes

I (1933) Surface Phenomena xxvIII (1963) Synthesis and Structure of Macromolecules II (1934) Aspects of Growth XXIX (1964) Human Genetics III (1935) Photochemical Reactions XXX (1965) Sensory Receptors IV (1936) Excitation Phenomena XXXI (1966) The Genetic Code V (1937) Internal Secretions XXXII (1967) Antibodies VI (1938) Protein Chemistry XXXIII (1968) Replication of DNA in Microorganisms VII (1939) Biological Oxidations XXXIV (1969) The Mechanism of Protein Synthesis VIII (1940) Permeability and the Nature of Cell Membranes XXXV (1970) Transcription of Genetic Material IX (1941) Genes and Chromosomes: Structure and Organiza- XXXVI (1971) Structure and Function of Proteins at the tion Three-dimensional Level X (1942) The Relation of Hormones to Development XXXVII (1972) The Mechanism of Muscle Contraction XI (1946) Heredity and Variation in Microorganisms XXXVIII (1973) Chromosome Structure and Function XII (1947) Nucleic Acids and Nucleoproteins XXXIX (1974) Tumor Viruses XIII (1948) Biological Applications of Tracer Elements XL (1975) The Synapse XIV (1949) Amino Acids and Proteins XLI (1976) Origins of Lymphocyte Diversity XV (1950) Origin and Evolution of Man XLII (1977) Chromatin XVI (1951) Genes and Mutations XLIII (1978) DNA: Replication and Recombination XVII (1952) The Neuron XLIV (1979) Viral Oncogenes XVIII (1953) Viruses XLV (1980) Movable Genetic Elements XIX (1954) The Mammalian Fetus: Physiological Aspects of XLVI (198l) Organization of the Cytoplasm Development XLVII (1982) Structures of DNA XX (1955) Population Genetics: The Nature and Causes of XLVIII (1983) Molecular Neurobiology Genetic Variability in Population XLIX (1984) Recombination at the DNA Level XXI (1956) Genetic Mechanisms: Structure and Function L (1985) Molecular Biology of Development XXII (1957) Population Studies: Animal Ecology and De- LI (1986) Molecular Biology of Homo sapiens mography LII (1987) Evolution of Catalytic Function XXIII (1958) Exchange of Genetic Material: Mechanism and LIII (1988) Molecular Biology of Signal Transduction Consequences LIV (1989) Immunological Recognition XXIV (1959) Genetics and Twentieth Century Darwinism LV (1990) The Brain XXV (1960) Biological Clocks LVI (1991) The Cell Cycle XXVI (1961) Cellular Regulatory Mechanisms LVII (1992_) The Cell Surface XXVII (1962) Basic Mechanisms in Animal Virus Biology Front Cover (Paperback): The scaffold/loop model can explain chromosome bands. This extended scaffold/loop model displays the unfolded, hypothetical chromatid fiber on the left; this fiber serves to explain the more compact metaphase chromosome on the right. (For details, see Saitoh and Laemmli, p. 757, this volume.) Back Cover (Paperback): Electron density of the mixed sequence nucleosome core particle. (For details, see Richmond et al., p. 268, this volume.) Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cold Spring Harbor Laboratory for libraries and other users registered with the Copyright Clearance Center (CCC) Transactional Reporting Service, provided that the base fee of $5.00 per article is paid directly to CCC, 21 Congress St., Salem MA 01970. [0-87969-065-8/93 $5.00 + .00]. This consent does not extend to other kinds of copying, such as copying for general distribution, for advertising or promotional purposes, for creating new collective works, or for resale. All Cold Spring Harbor Laboratory Press publications may be ordered directly from Cold Spring Harbor Laboratory Press, 10 Skyline Drive, Plainview, New York 11803. Phone: 1-800-843-4388 in Continental U.S. and Canada. All other locations (516)349-1930. FAX: (516)349-1946. Symposium Participants

AGUINAGA, PILAR, Comprehensive Sickle-Cell BERMAN, JUDITH, Dept. of Botany, University of Center, Meharry Medical College, Nashville, Minnesota, St. Paul Tennessee BERNARDI, GIORGIO, Dept. of Molecular Genet- ALBERTS, BRUCE, Dept. of Biochemistry and Bio- ics, Institut Jacques Monod, Paris, France physics, University of California, San Fran- BERRY, MEERA, Lab. of Gene Structure and Ex- cisco pression, National Institute for Medical Re- ALBERTSON, DONNA, Molecular Genetics Unit, search, The Ridgeway, London, United MRC Laboratory of Molecular Biology, Kingdom Cambridge, United Kingdom BIANCHI, ALLESSANDRO, Rockefeller University, ALFANO, CHRISTINE,Dept. of Biochemistry, Stan- New York, New York ford Medical Center, Stanford, California B1ESSMANN, HARALD, Developmental Biology ANAND, RAKESH, Zeneca, V.I.M., Macclesfield, Center, University of California, Irvine Cheshire, United Kingdom BIRD, ADRIAN, Institute of Cell and Molecular ANTEQUERA, FRANCISCO, Dept. of Cell and Molec- Biology, Medical Research Council, Univer- ular Biology, Edinburgh University, Scot- sity of Edinburgh, Scotland, United Kingdom land, United Kingdom BIRD, LOUISE, Dept. of Biochemistry, Oxford AZORIN, F., Investigacion y Desarrollo, Consejo University, United Kingdom Superior de lnvestigaciones Cientifica, Bar- BLACKBURN, ELIZABETH, Dept. of Microbiology celona, Spain and Immunology, University of California, BACCHETTI, SILVIA, Dept. of Pathology, McMas- San Francisco ter University, Hamilton, Ontario, Canada BLENNOW, ELIZABETH,Dept. of Clinical Genetics, BAJALICA, SVETLANA, Dept. of Clinical Genetics, Karolinska Hospital, Stockholm, Sweden Karolinska Institute, Stockholm, Sweden BONNER, WILLIAM, NCI, National Institutes of BAR, ISABELLE, Dept. of Physiology, Facult6 de Health, Bethesda, Maryland M6decin, FUNDP Medical School, Namur, BORST, PIET, Dept. of Molecular Biology, Nether- Belgium lands Cancer Institute, Amsterdam BAVYKIN, SERGEI, Dept. of Biological Chemistry, BOTCHAN, MICHAEL, Dept. Molecular and Cel- University of California, Davis lular Biology, University of California, Ber- BECK, ANITA, Dept. of Molecular Biotechnology, keley University of Washington, Seattle BOURBONNII~RE, MARTIN, Dept. of Neurology and BEDOYAN, JIRAIR, Biophysics Research Division, Neurosurgery, McGill University, Montreal, University of Michigan, Ann Arbor Quebec, Canada BEHN-KRAPPA, ANNETT, Dept. of Virology, Uni- BOYES, JOAN, Dept. of Molecular Biology, versity of Cologne, Germany NIDDK, National Institutes of Health, BELL, STEPHEN, Cold Spring Harbor Laboratory, Bethesda, Maryland Cold Spring Harbor, New York BRENNER, SYDNEY, Scripps Research Institute, La BELLON, STEVEN, Dept. of Molecular Biophysics Jolla, California and Dept. of Molecular Biol- and Biochemistry, Yale University, New ogy, Molecular Genetics Unit, MRC Labora- Haven, Connecticut tory, Cambridge, United Kingdom BELMAAZA, ABDELLAH, Dept. of Research and BRESNICK, EMERY, Dept. of Molecular Biology, Development, Canadian Red Cross Society, National Institutes of Health, Bethesda, Montreal, Quebec, Canada Maryland BENGAL, EYAL, Dept. of Molecular Biology and BREWER, BONITA, Dept. of Genetics, University Virology, Salk Institute for Biological of Washington, Seattle Studies, San Diego, California BROWN, KAREN, Dept. of Biochemistry, Oxford BERG, BARBARA, Dept. of Molecular Genetics University, United Kingdom and Cell Biology, University of Chicago, Il- BROWN,WILLIAM, Dept. of Biochemistry, Oxford linois University, United Kingdom V vi SYMPOSIUM PARTICIPANTS

BUCAN, MAJA, Dept. of Psychiatry, University of COHEN, DANIEL, Centre d'Etude du Polymor- Pennsylvania, Philadelphia phisme Humain, Paris, France BURGOYNE, L.A., School of Biological Sciences, COUNTER, CHRIS, Dept. of Pathology and Bio- Flinders University of South Australia, chemistry, McMaster University, Hamilton, Adelaide Ontario, Canada BURLEY, STEPHEN, Dept. of Molecular Biophysics, COUNTRYMAN, JILL, Dept. of Molecular Bio- Rockefeller University, New York, New York physics and Biochemistry, Yale University, BUSTIN, M~CHAEL, Lab. of Molecular Car- New Haven, Connecticut cinogenesis, NCI, National Institutes of CRANE-ROBINSON, COLYN, Dept. of Biophysics, Health, Bethesda, Maryland University of Portsmouth, United Kingdom CARBON, JOHN, Dept. of Biological Sciences, Uni- CREMER, THOMAS, Dept. of Human Genetics, versity of California, Santa Barbara University of Heidelberg, Germany CARDOSO, MARIACRISTINA, Dept. of Cardiology, CROSS, SALLY,Dept. of Cell and Molecular Biolo- Children's Hospital, Boston, Massachusetts gy, University of Edinburgh, Scotland, CAREY, NESSA, Dept. of Anatomy, Charing Cross United Kingdom and Westminister Medical School, London, CROTHERS, DONALD, Dept. of Chemistry, Yale United Kingdom University, New Haven, Connecticut CARLSON, MARIAN, Dept. of Human Genetics, CUISSET, LAURENCE, Institut Cochin de Gen- Columbia University, New York, New York etique Moleculaire, Paris, France CARR, KIMBERLY,Nature, London, United King- DALRYMPLE, MICHAEL, Pharmaceutical Proteins, dom Ltd., Roslin, Scotland, United Kingdom CARTER, KENNETH, Dept. of Cell Biology, Uni- DASTUGUE, B., Dept. of Medical Biochemistry, versity of Massachusetts Medical Center, University of Auvergne, Clermont-Ferrand, Worchester France CEDAR, HOWARD, Dept. of Cellular Biochemistry, DA~A, SHOIBAL,Dept. of Molecular Biology and Hebrew University Hadassah Medical Cen- Biochemistry, University of California, Irvine ter, Jerusalem, Israel DE LANCE, TITIA, Rockefeller University, New CHAPMAN, VERNE, Dept. of Molecular/Cellular York, New York Biology, Roswell Park Memorial Institute, DE MASSY, BERNARD, University of Paris, Orsay, Buffalo, New York France CHARLEBOIS, TIMOTHY, Dept. of Mammalian and DEPAMPHILIS,MELVIN, Roche Institute of Molecu- Microbial Cell Sciences, Genetics Institute, lar Biology, Nutley, New Jersey Andover, Massachusetts DEBATISSE, MICHELLE,Dept. of Immunology, In- CHARTRAND, PIERRE, Dept. of Research and De- stitut Pasteur, Paris, France velopment, La SociGt6 Canadienne de la DEININGER, PRESCOTT, Dept. of Biochemistry and Croix-Rouge, Montreal, Quebec, Canada Molecular Biology, Louisiana State Universi- CHEN, JINGWEN, Dept. of Cell Biology, Glaxo ty Medical Center, New Orleans Inc., Research Triangle Park, North Carolina DELPECH, MARC, Institut Cochin de Genetique CHEN, T.R., 12301 Parklawn Dr., Rockville, Moleculaire, Paris, France Maryland DERNBURG, ABBY, Dept. of Biochemistry and CHEN, ZHIJIAN, Dept. of Molecular Biology, Bax- Biophysics, University of California, San ter, Santa Ana, California Francisco CHENG, XIAODONG, Cold Spring Harbor Labora- DETWEILER, CORRIE, Dept. of Microbiology and tory, Cold Spring Harbor, New York Immunology, University of California, San CHESNOKOV, IGOR, Dept. of Genetics, University Francisco of California, Davis DEVl, C.V. RAMANA, Institute of Genetics, Hy- CHIN, GILBERT, Science, Washington, D.C. derabad, India CHOl, JUNG LIM, Dept. of Pediatric Oncology, DILLON, NIALL, Lab. of Gene Structure and Ex- Fred Hutchinson Cancer Research Center, pression, National Institute for Medical Re- Seattle, Washington search, London, United Kingdom CHUNG, JAY, Dept. of Molecular Biology, Nation- DOBI, ALBERX, LDN, NICHD, National Institutes al Institutes of Health, Bethesda, Mary- of Health, Bethesda, Maryland land DOBROVIC, ALEXANDVR, Dept. of Haematology/ CLARKE, LOUISE, Dept. of Biological Sciences, Oncology, Queen Elizabeth Hospital, Wood- University of California, Santa Barbara ville, South Australia SYMPOSIUM PARTICIPANTS vii

DROGE, PETER, Dept. of Biology, University of FRAGOSO, GILBERTO, Lab. of Molecular Virology, Konstanz, Germany NCI, National Institutes of Health, Bethesda, DUJON, BERNARD, Dept. of Molecular Biology, Maryland Institut Pasteur, Paris, France FRASHIER, GARY, Oncogene Science, Uniondale, EARNSHAW, WILLIAM, Dept. of Cell Biology and New York Anatomy, Johns Hopkins University, Balti- FREUDENREICH, CATHERINE, Dept. of Microbiol- more, Maryland ogy, Duke University Medical Center, Dur- EBRALIDSE, KONSTANTIN, Dept. of Biochemistry ham, North Carolina and Molecular Biology, Harvard University, FRIEDMAN, KATHERINE, Dept. of Genetics, Uni- Cambridge, Massachusetts versity of Washington, Seattle LID, JOSIANE, Dept. of Biological Chemistry, FURTH, MARK, Dept. of Molecular Sciences, John Hopkins University School of Medicine, Glaxo Research Institute, Research Triangle Baltimore, Maryland Park, North Carolina ELGIN, SARAH, Dept. of Biology, Washington GALL, JOSEPH, Dept. of Embryology, Carnegie University, St. Louis, Missouri Institution of Washington, Baltimore, Mary- ELLIS, JAMES, National Institute for Medical Re- land search, Medical Research Council, London, GARNER, MARK, LTPB/NICHD, National Insti- United Kingdom tutes of Health, Bethesda, Maryland EMERSON, BEVERLY,Dept. of Regulatory Biology, GASSER, SUSAN, Dept. of Cancer Research, Silk Institute for Biological Studies, San ISREC, Epalinges, Switzerland Diego, California GEETHANJALI, DORNADULA,Hospital for Genetic EMMERSON, PETER, Dept. of Biochemistry and Disease, Institute of Genetics, Begumpet, Genetics, Medical School, University of India Newcastle Upon Tyne, United Kingdom GENUARIO, ROBERT, Dept. of Cancer Research, ENGLER, PETER, Dept. of Molecular Genetics and Fox Chase Cancer Center, Philadelphia, Cell Biology, University of Chicago, Illinois Pennsylvania EPNER, ELLIOT, Dept. of Genetics, Fred Hutch- GEORGIEV, GEORGII, Institute of Gene Biology, inson Cancer Research Center, Seattle, Russian Academy of Sciences, Moscow Washington GERBI, SUSAN, Dept. of Biology and Medicine, FAIRMAN, MICAELA, MRC Radiobiology Unit, Brown University, Providence, Rhode Island Chilton, Didcot, Oxon, United Kingdom GERMAN, JAMES, Dept. of Human Genetics, New FARR, CHRISTINE, Dept. of Genetics, University York Blood Center, New York, New York of Cambridge, United Kingdom G1ULOTTO, ELENA, Dept. of Genetics and Micro- FEINGOLD, JAY, Bone Marrow Transplant Unit, biology, Universita di Pavia, Italy Rush University School of Medicine, GODSON, G. NIGEL, Dept. of Biochemistry, New Chicago, Illinois York University Medical Center, New York, FELSENFELD, GARY, Dept. of Molecular Biology, New York National Institutes of Health, Bethesda, GORDENIN, DMITRY, Dept. of Genetics, St. Peters- Maryland burg State University, Russia FERGUSON, DAVID, Dept. of Microbiology, Cot- GOTTSCHLING, DANIEL, Dept. of Molecular Ge- nell University Medical College, New York, netics and Cell Biology, University of New York Chicago, Illinois FERRE-D'AMARE, ADRIAN, Dept. of Molecular GRANGER, STEVE, Dept. of Molecular Biology Biophysics, Rockefeller University, New and Biology, University of California, Irvine York, New York GRAUSZ, DAVID, C.E.P.H.B., C.E.P. de L'Hom- FESTENSTEIN, RICHARD, Dept. of Molecular Im- me et de sa Biosphere, Paris, France munology, National Institute for Medical Re- GREEN, MICHAEL, Program in Molecular Medi- search, London, United Kingdom cine, University of Massachusetts Medical FLEISSNER, ERWIN, Division of Science and Mathe- Center, Worcester matics, Hunter College, CUNY, New York, GREIDER, CAROL, Cold Spring Harbor Labora- New York tory, Cold Spring Harbor, New York FORMOSA, TIMOTHY, Dept. of Biochemistry, Uni- GROSSCHEDL, RUDOLPH, Dept. of Microbiology versity of Utah, Salt Lake City and Immunology, University of California, FOULKES, J. GORDON, Dept. of Therapeutics, On- San Francisco cogene Science, Inc., Uniondale, New York GROSVELD, FRANK, Lab. of Gene Structure and viii SYMPOSIUM PARTICIPANTS

Expression, National Institute for Medical HILDEBRANDT, EMILY, Dept. of Molecular and Research, London, United Kingdom Cellular Biology, University of California, GRUNSTEIN, MICHAEL, Molecular Biology Insti- Berkeley tute, University of California, Los Angeles HIRAOKA,YASUSHI, Dept. of Communications Re- GUNARATNE, PREETHI, Dept. of Molecular Ge- search, Kansai Advanced Research Center, netics, Baylor College of Medicine, Houston, Kobe, Japan Texas HIROSE, SUSUMU, Dept. of Developmental Biolo- HAGER, GORDON, Laboratory of Molecular Virol- gy, National Institute of Genetics, Mishima, ogy, National Cancer Institute, Bethesda, Japan Maryland HIRST, MARK, Dept. of Molecular Genetics, John HAGSTROM, KIRSTEN,Dept. of Molecular Biology, Radcliffe Hospital, Oxford, United King- Princeton University, Princeton, New Jersey dom HAMLIN, JOYCE, Dept. of Biochemistry, Universi- HOLLER, EGGE~JARD, Dept. of Biophysics and ty of Virginia School of Medicine, Charlottes- Physical Biochemistry, Universit/it Regens- ville burg, Germany HANISH, JOHN, Dept. of Cell Biology and Ge- HOLLOWAY, SANDRA, Dept. of Physiology, Uni- netics, Rockefeller University, New York, versity of California, San Francisco New York HOOD, LEROY, Dept. of Molecular Biotechnol- HARDISON, ROSS, Dept. of Molecular and Cell ogy, University of Washington, Seattle Biology, Pennsylvania State University, Uni- HORIUCHI, TAKASHI, National Institute for Basic versity Park, Pennsylvania Biology, Myodaijichou, Okazaki, Japan HARLEY, CALVIN,Dept. of Biochemistry, McMas- HOWE, CHIN, Wistar Institute, Philadelphia, ter University, Hamilton, Ontario, Canada Pennsylvania HASSAN, A.B., Sir William Dunn School of HYRIEN, OLlVIER, Dept. of Molecular Embryolo- Pathology, University of Oxford, United gy, Institut Jacques Monod, Paris, France Kingdom ILIAKIS, GEORGE, Dept. of Radiation Oncology HASTINGS, PHILLIP, Dept. of Genetics, University and Nuclear Medicine, Thomas Jefferson of Alberta, Edmonton, Canada University, Philadelphia, Pennsylvania HAYASHIZAKI, YOSHIHIDE, Gene Bank, RIKEN IMBALZANOM,ANTHONY, Dept. of Molecular Biol- Tsukuba Life Science Center, Japan ogy, Massachusetts General Hospital, Boston HECK, MARGARET, Dept. of Cell Biology and ISH-HOROWlCZ, DAVID, Dept. of Zoology, ICRF Anatomy, Johns Hopkins Medical School, Developmental Biology Unit, University of Baltimore, Maryland Oxford, United Kingdom HENDERSON, Scott C., Cold Spring Harbor Lab- ISHIKAWA, FUYUKI, Dept. of Life Science, Tokyo oratory, Cold Spring Harbor, New York Institute of Technology, Japan HENDRICH, BRIAN, Dept. of Genetics, Case West- JACKSON, AMANDA, Dept. of Human Immuno- ern Reserve University, Cleveland, Ohio genetics, Imperial Cancer Research Fund, HENG, HENRY, Dept. of Genetics, Hospital for London, United Kingdom Sick Children, Toronto, Ontario, Canada JACOB, FRANCOIS, Dept. of Molecular Biology, HENIKOFF, STEVEN, Howard Hughes Medical In- Institut Pasteur, Paris, France stitute, Fred Hutchinson Cancer Research JAENISCH, RUDOLF, Dept. of Biomedical Re- Center, Seattle, Washington search, Whitehead Institute, Cambridge, HERBERT, ALAN, Dept. of Biology, Massachusetts Massachusetts Institute of Technology, Cambridge JANKELEVICH, SHIRLEY, Dept. of Pediatrics, Yale HERR, WINSHIP, Cold Spring Harbor Laboratory, University School of Medicine, New Haven, Cold Spring Harbor, New York Connecticut HEWlTT, JANE, Dept. of Cell and Structural Biolo- JASIN, MARIA, Dept. of Cell Biology and Genetics gy, Manchester University Medical School, Program, Memorial Sloan-Kettering, New United Kingdom York, New York HIETER, PHILIP, Dept. of Molecular Biology and JAUCH, ANNA, Dept. of Human Genetics, Uni- Genetics, Johns Hopkins University, Balti- versity of Heidelberg, Germany more, Maryland JAVERZAT, JEAN-PAUL, Human Genetics Unit, HIGASHINAKAGAWA,TORU, Dept. of Developmen- Medical Research Council, Edinburgh, tal Biology, Mitsubishi Kasei Institute of Life United Kingdom Sciences, Tokyo, Japan JESUDASAN, RACHEL, Dept. of Hematology and SYMPOSIUM PARTICIPANTS ix

Oncology, Childrens Hospital, Los Angeles, Carolina Biotechnology Center, Research California Triangle Park JIANG, WEIDONG, Dept. of Biological Science, KREUZER, KENNETH, Dept. of Microbiology, University of California, Santa Barbara Duke University Medical Center, Durham, JONES, BEVERLY,Dept. of Human Genetics, Uni- North Carolina versity of Pennsylvania, Philadelphia KRNACIK, MICHAEL,Dept. of Cell Biology, Baylor J(3TTERMANN, RUTH, Whitehead Institute for Bio- College of Medicine, Houston, Texas medical Research, Cambridge, Massachu- LAEMMLI, ULRICH, Dept. of Molecular Biology, setts University of Geneva, Switzerland KABACK, DAVID, Dept. of Genetics, UMDNJ- LAIRD, CHARLES, Dept of Zoology, University of New Jersey Medical School, Newark Washington, Seattle KADONAGA, JAMES, Dept. of Biology, University LANDER, ERIC, Whitehead Institute, Massachu- of California, San Diego setts Institute of Technology, Cambridge KAHMANN, REGINE, Institut ffir Genetik und LANGMORE, JOHN, Dept. of Biophysics, Universi- Mikrobiologie, Universit~it Mfinchen, Ger- ty of Michigan, Ann Arbor many LAWRENCE, JEANNE, Dept. of Cell Biology, Uni- KALOS, MICHAEL, Dept. of Basic Sciences, Fred versity of Massachusetts Medical School, Hutchinson Cancer Research Center, Seattle, Worcester Washington LEACH, DAVID, Dept. of Molecular Biology, Uni- KARPEN, GARY, MBVL, Salk Institute for Bio- versity of Edinburgh, Scotland, United King- logical Studies, San Diego, California dom KAWASAKI, KATSUMI, Dept. of Microbiology, LECHNER, JOHANNES, Dept. of Biochemistry, Uni- RIKEN, Saitama, Japan versit~it Regensburg, Germany KELLY, THOMAS, Dept. of Molecular Biology and LEE, GRACE, Dept. of Obstetrics and Gynecolo- Genetics, Johns Hopkins University, Balti- gy, Yale University, New Haven, Connecticut more, Maryland LEE, SEEWOO,Dept. of Biochemistry and Molecu- KESTI, TAPIO, Dept. of Biochemistry, University lar Biology, Louisiana State University Medi- of Oulu, Finland cal Center, Shreveport KIRUCHI, AKIHIKO, Mitsubishi-Kasei Institute of LEFFAK, MICHAEL, Dept. of Biochemistry and Life Sciences, Tokyo, Japan Molecular Biology, Wright State University, KIM, MOON, Dept. of Genetics and Biochemistry, Dayton, Ohio NIDDK, National Institutes of Health, LEONARD, MARK, Dept. of Mammalian and Mi- Bethesda, Maryland crobial Cell Sciences, Genetics Institute, An- KIPLING, DAVID, Dept. of Human Genetics, MRC dover, Massachusetts Laboratory, Western General Hospital, Edin- LEONHARDT, HEINRICH, Dept. of Cardiology, burgh, Scotland, United Kingdom Children's Hospital, Harvard Medical KIRK, KAREN, Dept. of Microbiology, University School, Boston, Massachusetts of California, San Francisco LEVlNE, MYRON, Dept. of Human Genetics, Uni- KLAR, AMAR, ABL-Basic Research Program, versity of Michigan, Ann Arbor Laboratory of Eukaryotic Gene Expression, LEWIS, CATHERINE, Genetics Program, NIGMS, Frederick, Maryland National Institutes of Health, Betbesda, KLECKNER, NANCY, Dept. of Biochemistry and Maryland Molecular Biology, Harvard University, LEWIS, PETER, Dept. of Biochemistry, University Cambridge, Massachusetts of Toronto, Ontario, Canada KLEIN, HANNAH, Dept. of Biochemistry, New LI, Xu, Howard Hughes Medical Center, Stan- York University Medical Center, New York, ford University Medical Institute, Stanford, New York California KLEIN, SHOSHANA, Dept. of Genetics, Hebrew LIANG, CHUN, Bio-Med Division, Brown Uni- University of Jerusalem, Israel versity, Providence, Rhode Island KODADEK, THOMAS, Dept. of Chemistry and Bio- LICHTER, PETER, Angewandte Tumorvirologie, chemistry, University of Texas, Austin German Cancer Research Center, Heidel- KOSHLAND, DOUGLAS,Dept. of Embryology, Car- berg, Germany negie Institution of Washington, Baltimore, LINDAHL, THOMAS, Clare Hall Laboratories, Im- Maryland perial Cancer Research Fund, South Mimms, KREUZER, HELEN, Education Program, North United Kingdom x SYMPOSIUM PARTICIPANTS

LITFLE, RANDALL, Dept. of Cell Biology, Albert versity School of Medicine, New Haven, Einstein College of Medicine, Bronx, New Connecticut York MATSUMOTO, KEN, Mitsubishi Kasel Institute of LIU, DONG FENG, Dept. of Anatomy and Cell Life Sciences, Tokyo, Japan Biology, McGill University, Montreal, MAYNE, LYNNE, Dept. of Biological Science, Traf- Quebec, Canada ford Centre for Medical Research, University LJUNGMAN, MATS, Dept. of Biological Sciences, of Sussex, United Kingdom Herrin Laboratories, Stanford University, MCEWAN, lAIN, Dept. of Biotechnology, Karolin- Stanford, California ska Institute, Huddinge, Sweden LOSICK, RICHARD,Dept. of Cellular and Develop- McMACKEN, ROGER, Dept. of Biochemistry, mental Biology, Harvard University, Cam- Johns Hopkins University, Baltimore, Mary- bridge, Massachusetts land Lu, JENNIFER, Dept. of Molecular Biology and MCMANUS, JOHN,William Dunn School of Pathol- Biochemistry, Yale University School of ogy, Oxford University, United Kingdom Medicine, New Haven, Connecticut MCPHERSON, CLIFTON, Dept. of Biochemistry, LUGER, KAROLIN, Institute of Molecular Biology, Brown University, Providence, Rhode Island Zurich, Switzerland MEEHAN, RICHARD, Dept. of Cell and Molecular LUNDBLAD,VICTORIA, Institute for Molecular Ge- Biology, Edinburgh University, Scotland, netics, Baylor College of Medicine, Houston, United Kingdom Texas MELLER,VtCTORIA, Dept. of Pharmacological Sci- LUSTIG, ARTHUR, Dept. of Molecular Biology, ences, State University of New York, Stony Memorial Sloan-Kettering, New York, New Brook York MIAKE-LYE, RYN, Cell, Cambridge, Massachusetts MACKAY, ALASTAIR, Dept. of Cell Biology and MICHAEL, NANCY, Dept. of Molecular Genetics Anatomy, Johns Hopkins University, Balti- and Cell Biology, University of Chicago, Il- more, Maryland linois MAEKAWA, HIDEAKI, Dept. of Radiation Control MILOT, ERIC, Dept. of Research and Develop- and Biology, National Institute of Health, ment, Canadian Red Cross, Montreal, Tokyo, Japan Quebec, Canada MAKAROV, VLADIMIR, Dept. of Biophysics Re- MISHRA, RAKESH, Dept. of Molecular Biophysics, search, University of Michigan, Ann Arbor University of Bordeaux, France MAKAROVA, OLGA, Dept. of Human Genetics, MIZUKAMI, TAMIO, Tokyo Research Laboratories, University of Michigan, Ann Arbor Kyowa Hakko Kogyo Co., Ltd., Japan MANDL, BIRGIT, Dept. of Molecular Pathology, MIZUUCHL KIYOSHI, Lab. of Molecular Biology, Research Institute of Molecular Pathology, NIDDK, National Institutes of Health, Vienna, Austria Bethesda, Maryland MANIATIS, TOM, Dept. of Biochemistry and Mo- MODRICH, PAUL, Dept. of Biochemistry, Duke lecular Biology, Harvard University, Cam- University Medical Center, Durham, North bridge, Massachusetts Carolina MANN, MELLISSA,Dept. of Zoology, University of MOEHS, CHARLES, Agricultural Research Service, Toronto, Ontario, Canada U.S. Department of Agriculture, Albany, MANN, RANDALL, Dept. of Molecular Biology, California Molecular Biology Institute, University of MORGANTE, MICHELE, Biotechnology Group, California, Los Angeles, DuPont Agricultural Products, Wilmington, MARCK, CHRISTIAN,Dept. of Cellular and Molec- Delaware ular Biology, S.B.G.M., Gif-Sur-Yvette, MORSE, RANDALL, NIDDKD, National Institutes France of Health, Bethesda, Maryland MARSHALL,WALLACE, Dept. of Biochemistry and MORTON, BRAD, Dept. of Cell Biology, Glaxo Biophysics, University of California, San Corporation, Research Triangle Park, North Francisco Carolina MARX, STEPHEN, Dept. of Molecular Biology and MOSELEY, CHANDAI, Dept. of Biomedical Sci- Genetics, Johns Hopkins University Medical ences, Meharry Medical College, Nashville, School, Baltimore, Maryland Tennessee MATERA, GREG, Dept. of Genetics, Yale Uni- MOUDRIANAKIS, EVANGELOS, Dept. of Biology, SYMPOSIUM PARTICIPANTS xi

Johns Hopkins University, Baltimore, Mary- PANDIT, NIKETAN, Max-Planck Institute for Mo- land lecular Genetics, Berlin, Germany MUKHERJEE, SUNIL, Dept. of Genetic Engineering PANDITA, TEJ, Dept. of Medical Oncology, M.D. and Biotechnology, UNIDO, New Delhi, Anderson Cancer Center, Houston, Texas India PANYUTIN, IGOR, Genetics and Biochemistry MULLER, MARTIN, Dept. of Molecular Biol- Branch, NIDDK, National Institutes of ogy, Princeton University, Princeton, New Health, Bethesda, Maryland Jersey PAR~:ES,V~NCENT, Dept of Molecular Cell Pathol- MURPHY, TERENCE, Dept. of Biology, University ogy, Royal Free Hospital School of Medicine, of California, San Diego London, United Kingdom NEDOSPASOV, SERGE1, LMI, BRMP, NCI, Fre- PARKS, SUKI, Science, Washington, D.C. derick Cancer Research and Development PARO, RENATO, Dept. of Molecular Biology, Center, Frederick, Maryland ZMBH, Heidelberg, Germany NER, SARBJIT, Dept. of Molecular Biology, Medi- PAULL, TANYA, Dept. of Biological Chemistry, cal Research Council, Cambridge, United Molecular Biology Institute, University of Kingdom California, Los Angeles NEUMAN, THOMAS, Dept. of Anatomy and Neuro- PERDIGAO, JOANA, Dept. of Molecular Genetics, biology, Colorado State University, Fort Col- Centro Citologia Experimental, Porto, Por- lins tugal NEUMANN, BJORN, Dept. of Molecular Pathology, PESEK, JOAN, Cold Spring Harbor Laboratory, Research Institute of Molecular Pathology, Cold Spring Harbor, New York Vienna, Austria PIKE, LISA, NIDDK, National Institutes of NEWLON, CAROL, Dept. of Microbiology and Mo- Health, Bethesda, Maryland lecular Genetics, UMD-New Jersey Medical PLUTA, ANN, Dept. of Cell Biology and Anatomy, School, Newark Johns Hopkins University School of Medi- NGAN,VIVIAN, Dept. of Biological Sciences, Uni- cine, Baltimore, Maryland versity of California, Santa Barbara POVlNELLI, CHRISTINE,Institute for Molecular Ge- NISHIZAWA, MASAFUMI, Dept. of Microbiology, netics, Baylor College of Medicine, Houston, Keio University School of Medicine, Tokyo, Texas Japan PRESTING, GERNOT, Plant Science Center, Cornell NORTH, GEOFFREY, Current Biology, London, University, Ithaca, New York United Kingdom PRICE, CAROLYN, Dept. of Chemistry, University OGAWA, HIDEYUKI, Dept. of Biology, Faculty of of Nebraska, Lincoln Science, Osaka University, Japan PRICE, CLIVE, Dept. of Molecular Biology and O~AWA, TOMOKO, Dept. of Biology, Osaka Uni- Biotechnology, University of Sheffield, versity, Toyonaka, Japan United Kingdom OHTA, KUNIHIRO, Dept. of Microbiology, PRUZINA, SARA, Gene Structure and Expression, RIKEN, Wako, Japan Medical Research Council, London, United OttYAMA, TAKASHI, Technology for the Earth, Kingdom Meiji Institute of Health Science, Odawara, PRYDE, FIONA, Dept. of Yeast Genetics, Radcliffe Japan Hospital, Institute of Molecular Medicine, OLSON, MAYNARD, Dept. of Molecular Biotech- Oxford, United Kingdom nology, University of Washington, Seattle PTASHNE, MARK, Dept. of Molecular Biology and ORLANDO, VALERIO, ZMBH, University of Biochemistry, Harvard University, Cam- Heidelberg, Germany bridge, Massachusetts ORTEGA, J. MIGUEL, Roche Research Center, RAMAKRISHNAN, VENKI, Dept. of Biology, Roche Institute of Molecular Biology, Nut- Brookhaven National Laboratory, Center for ley, New Jersey Structural Biology, Upton, New York OSLEY, MARYANN, Dept. of Molecular Biology, RAPPOLD, GUDRUN, Dept. of Human Genetics, Memorial Sloan-Kettering, New York, New University of Heidelberg, Germany York RECHSTEINER, THOMAS, Institut ffir Molekular- PALLADINO, FRANCESCA, Swiss Institute for Ex- biologie und Biophysik, ETH-Honggerberg, perimental Research, Epalinges, Switzer- Zurich, Switzerland land REINAGEL, PAMELA, Dept. of Biochemistry and xii SYMPOSIUM PARTICIPANTS

Molecular Biology, Harvard University, SCHVARTZMAN, JORGE, Biologicas, Centro de In- Cambridge, Massachusetts vestigaciones Biologicas (CSIC), Madrid, REINBERG, DANIEL, Dept. of Biochemistry, Spain UMDNJ-Robert Wood Johnson Medical SCHWABE, JOHN, Lab. of Molecular Biology, School, Piscataway, New Jersey Medical Research Council, Cambridge, RICHMOND, TIMOTHY, Institut ffir Molekular- United Kingdom biologie und Biophysik, ETH-Honggerberg, SCHWACHA, ANTHONY, Dept. of Biochemistry and Zurich, Switzerland Molecular Biology, Harvard University, RIED, THOMAS, Dept. of Human Genetics, Uni- Cambridge, Massachusetts versity of Heidelberg, Germany SCHWARTZ, DAVID, Dept. of Chemistry, New York RINE, JASPER, Dept. of Molecular and Cellular University, New York, New York Biology, University of California, Berkeley SCOTT, JOHN, Dept. of Biology, University of ROBBINS, VICTOR, Dept. of Biomedical Sciences, Hawaii, Hilo Meharry Medical College, Nashville, Tennes- SEDAT, JOHN, Dept. of Biochemistry, University see of California, San Francisco ROBERTS, RICHARD,New England Biolabs, Bever- SELKER, ERIC, Dept. of Cell and Molecular Biolo- ly, Massachusetts gy, University of Edinburgh, Scotland, ROBERTSON, MIRANDA, Garland Publishing, Mid- United Kingdom dlesex House, London, United Kingdom SELLERI, LICIA,Dept. of Molecular Genetics, Salk ROEDER, ROBERT, Dept. of Biochemistry and Institute for Biological Studies, La Jolla, Molecular Biology, Rockefeller University, California New York, New York SENGER, GABRIELE,Lab. of Human Cytogenetics, ROGGE, LARS, Dept. of Pathology, Stanford Uni- Imperial Cancer Research Fund, London, versity School of Medicine, Stanford, Califor- United Kingdom nia SHAMANSKI, FAY, Dept. of Cancer and Develop- ROSENBERG, SUSAN, Dept. of Molecular Oncolo- mental Biology, Wellcome/CRC Institute, gy, Cross Cancer Institute, University of Al- Cambridge, United Kingdom berta Medical School, Edmonton, Alberta, SHEWCHUK, BRIAN, Dept. of Molecular and Cell Canada Biology, Pennsylvania State University, Uni- ROYLE, NICOLA, Dept. of Genetics, University of versity Park Leicester, United Kingdom SHIMIZU, MITSUHIRO,Dept. of Analytical Chemis- RUBIN,BRIAN, Dept. of Microbiology, Cornell Uni- try, Tokyo College of Pharmacy, Japan versity Medical College, New York, New York SHORE, DAVID, Dept. of Microbiology, Columbia RUPPERT, SIEGFRIED,Dept. of Molecular and Cell University College of Physicians & Surgeons, Biology, Howard Hughes Medical Institute, New York, New York University of California, Berkeley SHORT, NICHOLAS,Nature, London, United King- SANCAR, AzIz, Dept. of Biochemistry and Bio- dom physics, University of North Carolina, SIGLER, PAUL, Dept. of Molecular Biophysics and Chapel Hill Biochemistry, Yale University, New Haven, SANCHEZ-SERRANO, Ibis, Dept. of Zoology and Connecticut Genetics, Iowa State University, Ames SIKORAV, JEAN-LOUIS, Dept. of Biochemistry and SANDELL, LISA, Fred Hutchinson Cancer Re- Molecular Genetics, C.E.A./CNRS, Saclay, search Center, Seattle, Washington France SCHEDL, PAUL, Dept. of Biology, Princeton Uni- SIMPSON, ROBERT, Dept. of Cellular and Develop- versity, Princeton, New Jersey mental Biology, NIDDK, National Institutes SCHERF, ARTHUR, Dept. of Experimental of Health, Bethesda, Maryland Parasitology, Institut Pasteur, Paris, France SINGH, DEVENDER,National Institute for Medical SCHILDKRAUT, CARL, Dept. of Cell Biology, Al- Research, Medical Research Council, Lon- bert Einstein College of Medicine, Bronx, don, United Kingdom New York SIPPEL, ALBRECHT, Dept. of Genetics, University SCHROTH, GARY, Dept. of Biochemistry and Bio- of Freiburg, Germany physics, Oregon State University, Corvallis SKALKA, ANNA MARIE, Institute for Cancer Re- SCHUTZ, GUNTHER, Institute of Cell and Tumor search, Fox Chase Cancer Center, Philadel- Biology, German Cancer Research Center, phia, Pennsylvania Heidelberg SMITH, CATHERINE, Dept. of Molecular Virology, SYMPOSIUM PARTICIPANTS xiii

National Cancer Institute, Bethesda, Mary- Biotechnology, University of Sheffield, land United Kingdom SMITH, JANET, Dept. of Food Science and Tech- TAYLOR, RONALD, Division of Computer Science nology, University of California, Davis and Technology, National Institutes of SNOWDEN, THOMAS, Biomedical College, Meharry Health, Bethesda, Maryland Medical College, Nashville, Tennessee TEl, HAJIME, Dept. of Medical Science, Universi- SOUTHGATE, CHRISTOPHER, Dept. of Biochemis- ty of Tokyo, Japan try, University of Massachusetts Medical TENCZA, MICHAEL, Dept. of Microbiology and School, Worcester Immunology, University of North Carolina, SPECTOR, DAVID, Cold Spring Harbor Laboratory, Chapel Hill Cold Spring Harbor, New York THOMAS, JEAN, Dept. of Biochemistry, University SPEICHER, MICHAEL, Dept. of Human Genetics, of Cambridge, United Kingdom University of Heidelberg, Germany TILGHMAN, SHIRLEY, Howard Hughes Medical In- SPRADL1NG, ALLAN, Dept. of Embryology, How- stitute, Princeton University, Princeton, New ard Hughes Medical Institute, Carnegie Insti- Jersey tution of Washington, Baltimore, Maryland TJIAN, ROBERT, Dept. of Molecular and Cell Biol- STAHL, FRANKLIN, Dept. of Molecular Biology, ogy, University of California, Berkeley University of Oregon, Eugene TESTY, THEA, Lineberger Comprehensive Cancer STAMMERS, MELANIE, Cambridge Laboratory, Research Center, University of North John Innes Centre, Norwich, United King- Carolina, Chapel Hill dom TOBINJANZEN, TAMMY, Genetics and Biochemis- STEIN, ARNOLD, Dept. of Biological Sciences, try Branch, National Institutes of Health, Purdue University, West Lafayette, Indi- Bethesda, Maryland ana TRASK, BARBARA,Dept. of Molecular Biotechnol- STEIN, JANET, Dept. of Cell Biology, University of ogy, University of Washington, Seattle Massachusetts Medical Center, Worcester TSE, DORIS, Dept. of Genetics and Development, STEITZ, THOMAS, Dept. of Molecular Biophysics Columbia University, New York, New York and Biochemistry, Howard Hughes Medical TURNER, BRYAN,Dept. of Anatomy, University of Institute, Yale University, New Haven, Con- Birmingham, Medical School, United King- necticut dom STERNGLANZ, ROLF, Dept. of Biochemistry and UI-TEI, KUMIKO, Dept. of Pharmacology, Nippon Cell Biology, State University of New York, Medical School, Tokyo, Japan Stony Brook URNOV, FYODOR, Dept. of Biology and Medicine, STILLMAN, BRUCE, Cold Spring Harbor Labora- Brown University, Providence, Rhode Island tory, Cold Spring Harbor, New York VALDIV[A, MANUEL, Dept. of Biochemistry and STOKES, DAVID, Institute for Cancer Research, Molecular Biology, Universidad de Cfidiz, Fox Chase Cancer Center, Philadelphia, Spain Pennsylvania VALENZUELA, MANUEL, Dept. of Biomedical Sci- STROUBOULIS, JOHN, National Institute for Medi- ence, Meharry Medical College, Nashville, cal Research, Medical Research Council, Tennessee London, United Kingdom VAN GRINSVEN, MART, Dept. of Biotechnology, SUBRAMANIAN, PREM, Dept. of Molecular Genet- Zaadunie B.V., Function Research, Enk- ics, Baylor College of Medicine, Houston, huizen, The Netherlands Texas VARMUS, HAROLD, Dept. of Microbiology, Uni- SUN, KEN, Dept. of Molecular Biophysics and versity of California, San Francisco Biochemistry, Yale University School of VARMUZA, SUE, Dept. of Zoology, University of Medicine, New Haven, Connecticut Toronto, Ontario, Canada SUROWY, CAROL, Dept. of Molecular Biology, VAZQUEZ, JULIO, Dept. of Molecular Biology, Sterling Winthrop Inc., Collegeville, Penn- Princeton University, Princeton, New Jersey sylvania VIDAL, MIGUELANGEL, CSIC, Centro de Inves- SVAREN, JOHN, Institut ffir Physiologische tigaciones Biologicas, Madrid, Spain Chemie, Universit/it M/inchen, Germany VILLASANTE, ALFREDO, Centro De Biologia Mo- TARUSCIO, DOMENICA, Dept. of Ultrastructures, lecular, UAM-CSIC, Cantoblanco, Madrid, Istituto Superiore de Sanita, Rome, Italy Spain TAYLOR, ELAINE,Dept. of Molecular Biology and VOLOSHIN, OLEG, Dept. of Genetics and Bio- xiv SYMPOSIUM PARTICIPANTS

chemistry, NIDDK, National Institutes of WOLD, MARC, Dept. of Biochemistry, University Health, Bethesda, Maryland of Iowa, Iowa City WAGA, SHOU, Cold Spring Harbor Laboratory, WOLFFE, ALAN, Dept. of Molecular Embryology, Cold Spring Harbor, New York NICHD, National Institutes of Health, WAHL, GEOFFREY, Dept. of Gene Expression, Bethesda, Maryland Salk Institute for Biological Studies, La Jolla, WOOD, RICHARD, Clare Hall Laboratories, Im- California perial Cancer Research Fund, Herts, United WANG, X. SUNNY, Dept.of Glycobiology, Amgen Kingdom Inc., Thousand Oaks, California WOODCOCK, CHRISTOPHER,Dept. of Biology, Uni- WARD, DAVID,Dept. of Genetics, Yale University versity of Massachusetts, Amherst School of Medicine, New Haven, Connec- WORKMAN, JERRY, Dept. of Molecular and Cell ticut Biology, Pennsylvania State University, Uni- WATANABE, SACHIHIKO, Research Laboratories, versity Park Shionogi & Co., Ltd., Osaka, Japan WUTHRICH, KURT, Dept. of Molecular Biology WATERSTON, ROBERT, Dept. of Genetics, and Biophysics, Swiss Federal Institute of Washington University School of Medicine, Technology, ETH-Honggerberg, Zurich, St. Louis, Missouri Switzerland WEBBER, ANDREA, Dept. of Molecular Biology, XU, CHANXING,Dept. of Molecular Biology, Uni- Princeton University, Princeton, New Jersey versity of California, Los Angeles WEINTRAUB, HAROLD, Dept. of Genetics, Fred YAGIL, GAD, Dept. of Cell Biology, Weizmann Hutchinson Cancer Research Center, Seattle, Institute of Science, Rehovot, Israel Washington YAMAMOTO, YUTAKA, Dept. of Cell Biology, Uni- WEISS, ALONA, Dept. of Cellular Biochemistry, versity of Basel, Switzerland Hebrew University, Hadassah Medical YANAGISAWA, SHUICHI, Dept. of Chemistry, Col- School, Jerusalem, Israel lege of Arts and Sciences, University of WEISSMAN, SHERMAN, Dept. of Genetics, Yale Tokyo, Japan University School of Medicine, New Haven, fANG, JUN, Dept. of Biological Sciences, Uni- Connecticut versity of Kentucky, Lexington WEST, STEVEN, Dept. of Genetic Recombination, YOON, HYE-Joo, Dept. of Biological Sciences, Imperial Cancer Research Fund, Herts, University of California, Santa Barbara United Kingdom ZAKIAN,VIRGINIA, Basic Sciences Division, Fred WHITBREAD, LEL, Roche Institute of Molecular Hutchinson Cancer Research Center, Seattle, Biology, Nutley, New Jersey Washington WIESENDANGER, BARBARA, Institut ffir Zellbiolo- ZALENSKY, ANDREI, Dept. of Biological Chemis- gie, ETH-Honggerberg, Zurich, Switzerland try, University of California School of Medi- WILLARD~ HUNTINGTON, Dept. of Genetics, Cen- cine, Davis ter for Human Genetics, Case Western Re- mARLING, DAVID, Dept. of Molecular Biology, serve University, Cleveland, Ohio SRI International, Menlo Park, California WINDLE, BRAD, Dept. of Molecular Biology, Can- ZONG, RuI-TING, Dept. of Pathology, University cer Therapy and Research Center, San An- of Texas Southwestern Medical Center, Dal- tonio, Texas las WOLBERGER, CYNTHIA, Dept. of Biophysics and ZUCCHI, ILEANA, CNR, Istituto Tecnologie Bio- Biophysical Chemistry, Johns Hopkins Uni- mediche Avanzate, Milano, Italy versity School of Medicine, Baltimore, Mary- land ~2~,..~ .._~'.~- ~'k,~" '-," L..~"~

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Undoubtedly, the discovery of the structure of the double helix in 1953 by James Watson and Francis Crick will be recorded as the foremost discovery in biology in this century. In just 40 years, the science of DNA has progressed to the stage where much is known about how genetic information is copied, transcribed, and organized. Moreover, gene therapy is now a reality, and a project to determine the complete sequence of the genomes of a number of organisms is well under way. It thus seemed natural to hold the 1993 Cold Spring Harbor Symposium, our 58th, on the topic of DNA. However, there were many celebratory meetings around the globe in honor of the 40 years of DNA, and we felt it was more appropriate to use the occasion to celebrate another significant milestone: Jim Watson's 25th year as Director of the Cold Spring Harbor Laboratory. The Laboratory and, indeed, the entire scientific community have been more than fortunate to have Jim Watson as the Director of the Laboratory for the past quarter century; he has revitalized this prominent scientific institution in an unprecedented way. Particularly significant has been Jim's recognition of the importance of the Laboratory's maintaining a high-quality educational program that includes scientific meetings and laboratory courses. In many respects, it is this program that makes the Laboratory unique and an exciting place to do science. Under Jim's direction, the meetings and course programs at the Laboratory have expanded and flourished so that today they have an impact on virtually all aspects of biology and medicine. We are pleased that as Jim steps down as Director, he will continue to guide the Laboratory as its first President. The flagship of the educational program is the annual Symposium. Because of the impact of DNA on biology, many Symposia have focused on topics that overlapped with this year's meeting. Most notable among these was the 1977 Symposium on chromatin, where the discovery of pre-mRNA splicing and split genes was announced. It is therefore quite fitting that the 1993 Nobel Prize for Physiology and Medicine was awarded to Richard Roberts and Philip Sharp for their role in this discovery. Rich Roberts was one of the key investigators in a multi-labcratory collaboration at Cold Spring Harbor that led to this important discovery, and we are happy to note that Phil Sharp, currently at MIT, is also a former Laboratory staff member. The topics covered at this Symposium ranged from the structure of DNA itself to the structure of complete genomes, and everything in between. I was most pleased and honored to have Bruce Alberts as the co-organizer of this meeting. Additional advice and help were obtained from Shirley Tilghman, Bob Tjian, and Dan Gottschling. The meeting was held from June 2 to June 9, 1993 and had 415 participants, 95 talks, and 145 poster presentations. The first night, marking Jim Watson's 25 years as Director, was highlighted by fascinating and entertaining talks by Franqois Jacob, Sydney Brenner, Mark Ptashne, and Robert Tjian and by the presentation to Jim of a collage of photographs of Laboratory staff and a magnificent 15-foot-tall bronze sculpture of the double helix created by the local artist Charles Reina. The week of exciting science was capped by a masterful summary presented by Hal Weintraub, who is one of the leading innovators in the field of DNA and chromosomes. Essential funds to hold this meeting were generously provided by the National Cancer Institute, the National Institute of Child Health and Human Development, and the National Institute of General Medical Sciences (all divisions of the National Institutes of Health); the National Science Foundation; and the U.S. Department of Energy, Office of Health and Environmental Research. In addition, the generous support of the following corporate sponsors is appreciated: Akzo Pharma International B.V.; American Cyanamid Company; Amgen Inc. ; Applied Biosystems, Inc. ; BASF Bioresearch Corporation; Becton Dickinson and Company; Bristol-Myers Squibb Company; Chugai Pharmaceutical Co., Ltd.; Diagnos- tic Products Corporation; The Du Pont Merck Pharmaceutical Company; Forest Lab- oratories, Inc.; Genentech, Inc.; Glaxo; Hoffmann-La Roche Inc.; Johnson & Johnson; Kyowa Hakko Kogyo Co., Ltd.; Life Technologies, Inc.; MetPath; Millipore Corporation; Monsanto Company; New England BioLabs, Inc.; Oncogene Science, Inc.; Pall Corpora- tion; Perkin-Elmer; Pfizer Inc.; Sandoz Research Institute; Schering-Plough Corporation; xix xx FOREWORD

SmithKline Beecham Pharmaceuticals; Sterling Winthrop Inc.; Sumitomo Pharmaceuticals Co., Ltd.; Takeda Chemical Industries. Ltd.; Toyobo Co., Ltd.; The Upjohn Company; and Wyeth-Ayerst Research. I thank the efficient staff in our Meetings Office, particularly Barbara Ward who has headed the Meetings Office for 18 years and retires this year, as well as Diane Tighe, Mikki McBride, and Andrea Stephenson for handling all the administrative aspects. Herb Parsons and his staff provided excellent audiovisual assistance. The organization of this meeting greatly relied on the marvelous work of my assistant Delia Costello, who made this time- consuming task a pleasure. Finally, it was again a pleasure to work with the efficient Publications office, under the direction of John Inglis, particularly Nancy Ford, Patricia Barker, and Joan Ebert. Their diligence and talents made this volume possible.

Bruce Stillman January 24, 1994 Contents

Symposium Participants V Foreword xix

Gene Expression Chromatin Structure of Transcriptionally Active Genes D. Clark, M. Re#man, V. Studitsky, J. Chung, H. Westphal, E. Lee, and G. Felsenfeld Regulation of Human Globin Gene Switching F. Grosveld, M. Antoniou, M. Berry, E. de Boer, N. Dillon, J. Ellis, P. Fraser, J. Hurst, A. Imam, D. Meijer, S. Philipsen, S. Pruzina, J. Strouboulis, and D. Whyatt 7 Chromatin Structure of the /3-Globin Chromosomal Domain in Adult Chicken Erythrocytes A. Verreault and J.O. Thomas 15 Structural-Functional Organization of Chromosomal DNA Domains S.V. Razin, R. Hancock, O. larovaia, O. Westergaard, L Gromova, and G.P. Georgiev 25 Chromatin Domains Constitute Regulatory Units for the Control of Eukaryotic Genes A.E. Sippel, G. Schiller, N. Faust, H. Saueressig, A. Hecht, and C. Bonifer 37 Genetic and Molecular Analysis of Chromatin Domains J. Vazquez, G. Farkas, M. Gaszner, A. Udvardy, M. Muller, K. Hagstrom, H. Gyurkovics, L. Sipos, J. Gausz, M. Galloni, L Hogga, F. Karch, and P. Schedl 45 Generation of Transgenic Mice with Yeast Artificial Chromosomes L. Montoliu, A. Schedl, G. Kelsey, P. Lichter, Z. Larin, H. Lehrach, and G. Schlitz 55 Influence of Chromatin Structure on the Binding of Transcription Factors to DNA G.L. Hager, T.K. Archer, G. Fragoso, E.H. Bresnick, Y. Tsukagoshi, S. John, and C.L. Smith 63 The High Mobility Group Protein HMG I(Y) Is an Essential Structural Component of a Virus-inducible Enhancer Complex D. Thanos, W. Du, and T. Maniatis 73 Role of Chromatin Structure in Regulating Gene Expression: The hsp26 Gene of Drosophila melanogaster S.C.R. Elgin, H. Granok, Q. Lu, and L.L. Wallrath 83 Role of Enhancer Sequences in Regulating Accessibility of DNA in Nuclear Chromatin T. Jenuwein, W. Forrester, and R. Grosschedl 97 Control of Antigenic Variation in African Trypanosomes P. Borst, J.H. Gommers- Ampt, M.J.L. Ligtenberg, G. Rudenko, R. Kieft, M.C. Taylor, P.A. Blundell, and F. van Leeuwen 105

Transcription of DNA and Chromatin DNA Bending in Transcription Initiation J.D. Kahn and D.M. Crothers 115 X-ray Crystallographic Studies of Eukaryotic Transcription Factors S.K. Burley, K.L. Clark, A. Ferr~-D'Amar~, J.L. Kim, and D.B. Nikolov 123 Stereochemistry of Specific Steroid Receptor-DNA Interactions W. Xu, I. Alroy, L.F. Freedman, and P.B. Sigler 133 The Cocrystal Structures of Two Zinc-stabilized DNA-hinding Domains Illustrate Different Ways of Achieving Sequence-specific DNA Recognition J.W.R. Schwabe, L. Fairall, L. Chapman, J.T. Finch, R.N. Dutnall, and D. Rhodes 141 Hydration of Biological Macromolecules in Solution: Surface Structure and Molecular Recognition K. Wiithrich 149 Structure and DNA Binding of the Yeast MATa2 Homeodomain C. Wolberger 159 Combinatorial Control of Transcription: The Herpes Simplex Virus VP16-induced Complex A.C. Wilson, M.A. Cleary, J.-S. Lai, K. LaMarco, M.G. Peterson, and W. Herr 167 Coactivators and TAFs: A New Class of Eukaryotic Transcription Factors That Connect Activators to the Basal Machinery N. Tanese and R. Tjian 179 xxi xxii CONTENTS

The Cycling of RNA Polymerase II during Transcription L. Zawel, H. Lu, L.J. Cisek, J.L. Corden, and D. Reinberg 187 How Eukaryotic Transcription Activators Increase Assembly of Preinitiation Complexes B. Choy, S.G.E. Roberts, L.A. Griffin, and M.R. Green 199 Biochemical Analysis of the Role of Chromatin Structure in the Regulation of Tran- scription by RNA Polymerase II R.T. Kamakaka and J.T. Kadonaga 205 Nucleosome Cores and Histone H1 in the Binding of GAL4 Derivatives and the Reactivation of Transcription from Nucleosome Templates In Vitro L.-J. Juan, P.P. Walter, LC.A. Taylor, R.E. Kingston, and J.L. Workman 213 Transcription Factor Access to DNA in the Nucleosome A.P. Wolffe, G. Almouzni, K. Ura, D. ['russ, and J.J. Hayes 225 Nucleosome Positioning and Transcription R.T. Simpson, S.Y. Roth, R.H. Morse, H.-G. Patterton, J.P. Cooper, M. Murphy, M.P. Kladde, and M. Shimizu 237 Histones and the Regulation of Heterochromatin in Yeast J.S. Thompson, A. Hecht, and M. Grunstein 247 Role of Yeast SNF and SWI Proteins in Transcriptional Activation B.C. Laurent, I. Treich, and M. Carlson 257

Genome Structure Studies of Nucleosome Structure T.J. Richmond, T. Rechsteiner, and K. Luger 265 Structure of the Histone Octamer Core of the Nucleosome and Its Potential Interactions with DNA E.N. Moudrianakis and G. Arents 273 Functions for DNA Methylation in Vertebrates A.P. Bird 281 Parental Imprinting of the H19 and Igf2 Genes in the Mouse S.M. Tilghman, M.S. Bartolomei, A.L. Webber, M.E. Brunkow, J. Saam, P.A. Leighton, K. Pfeifer, and S. Zemel 287 DNA Methylation, Genomic Imprinting, and Mammalian Development E. Li, C. Beard, A.C. Forster, T.H. Bestor, and R. Jaenisch 297 Allele-specific Structures in the Mouse Igf2-H19 Domain M. Ariel, S. Selig, M. Brandeis, D. Kitsberg, T. Kafri, A. Weiss, I. Keshet, A. Razin, and H. Cedar 307 Epigenetic and Chromosomal Control of Gene Expression: Molecular and Genetic Analysis of X Chromosome Inactivation H.F. Willard, C.J. Brown, L. Carrel, B. Hendrich, and A.P. Miller 315 Dissection of the Signal for DNA Methylation in the ~'-'ORegion of Neurospora E.U. Selker, G.A. Richardson, P.W. Garrett-Engele, M.J. Singer, and V. Miao 323 Crystal Structure of the HhaI DNA Methyltransferase X. Cheng, S. Kumar, S. Klimasauskas, and R.J. Roberts 331 Human and Mouse T-Cell-receptor Loci: The Importance of Comparative Large-scale DNA Sequence Analyses L. Hood, B.F. Koop, L. Rowen, and K. Wang 339 Criterion for the Completeness of Large-scale Physical Maps of DNA M.V. Olson and P. Green 349 Mapping and Sequencing the Nuclear Genome of the Yeast Saccharomyces cerevisiae: Strategies and Results of the European Enterprise B. Dujon 357 The Genome of the Nematode Caenorhabditis elegans R. Waterston, R. Ainscough, K. Anderson, M. Berks, D. Blair, M. Connell, J. Cooper, A. Coulson, M. Craxton, S. Dear, Z. Du, R. Durbin, A. Favetlo, L. Fulton, P. Green, N. Hattoran, T. Hawkins, L. Hillier, C. Huynh, L. Johnston, J. Kershaw, J. Kirsten, Y. Kozono, N. Laister, P. Latreille, B. Mortimore, D. Panussis, C. Percy, L. Rifkin, A. Roopra, R. Shownkeen, N. Smaldon, A. Smith, M. Smith, R. Staden, J. Sulston, J. Thierry-Mieg, M. Vaudin, K. Vaughan, L. Weinstock, R. Wilson, and P. Wohldmann 367 Integrated Mapping across the Whole Human Genome I. Chumakov, C. BellannO- Chantelot, I. LeGall, and D. Cohen 377

Replication of the Genome The Replicon: Thirty Years Later F. Jacob 383 Transcription Stimulates the Establishment of Bidirectional A DNA Replication In Vitro B. Learn, A.W. Karzai, and R. McMacken 389 Site-specific DNA-binding Proteins Important for Replication and Transcription Have Multiple Activities R. Li, L. Yang, E. Fouts, and M.R. Botchan 403 CONTENTS xxiii

Analysis of Replication Origin Function on Chromosome III of Saccharomyces cerevisiae C.S. Newlon, L Collins, A. Dershowitz, A.M. Deshpande, S.A. Green- feder, L.Y. Ong, and J.F. Theis 415 The Topography of Chromosome Replication in Yeast B.J. Brewer, J.D. Diller, K.L. Friedman, K.M. Kolor, M.K. Raghuraman, and W.L. Fangman 425 The Replicon Model and Eukaryotic Chromosomes S.P. Bell, Y. Marahrens, H. Rao, and B. Stillman 435 A Transcriptional Silencer as a Specialized Origin of Replication That Establishes Functional Domains of Chromatin C.A. Fox, S. Loo, D.H. Rivier, M.A. Foss, and J. Rine 443 The Mechanism of Fission Yeast Mating-type Interconversion: Evidence for Two Types of Epigenetically Inherited Chromosomal Imprinted Events A.J.S. Klar and M.J. Bonaduce 457 Initiation of Replication at a Mammalian Chromosomal Origin J.L. Hamlin, P.J. Mosca, P.A. Difkwel, and H.-B. Lin 467 Site-specific Initiation of DNA Replication in Metazoan Chromosomes and the Role of Nuclear Organization D.M. Gilbert, H. Miyazawa, F.S. Nallaseth, J.M. Ortega, J.J. Blow, and M.L. DePamphilis 475 DNA Amplification in DNA Puff II/9A of Sciara coprophila S.A. Gerbi, C. Liang, N. Wu, S.M. DiBartolomeis, B. Bienz-Tadmor, H.S. Smith, and F.D. Urnov 487 Two DNA Polymerases: HIV Reverse Transcriptase and the Klenow Fragment of Escherichia coli DNA Polymerase I T.A. Steitz, S. Smerdon, J. Jiiger, J. Wang, L.A. Kohlstaedt, J.M. Friedman, L.S. Beese, and P.A. Rice 495

Recombination, Repair, and Genome Stability Role of Gin and FIS in Site-specific Recombination P. Merker, G. Muskhelishvili, A. Deufel, K. Rusch, and R. Kahmann 505 Target Site Selection in Transposition of Phage Mu M. Mizuuchi and K. Mizuuchi 515 Late Steps in Genetic Recombination: Branch Migration and Holliday Junction Res- olution by RuvA, RuvB, and RuvC Proteins S.C. West, I.R. Tsaneva, K. Hiom, and F.E. Benson 525 Retroviral Integration Machinery as a Probe for DNA Structure and Associated Proteins H.-P. Miitter, P.M. Pryciak, and 1-I.E. Varmus 533 Chiasma Interference and the Distribution of Exchanges in Drosophila me&no- gaster R. Lande and 17. W. Stahl 543 Potential Advantages of Unstable Interactions for Pairing of Chromosomes in Meiotic, Somatic, and Premeiotic Cells N. Kleckner and B.M. Weiner 553 RecA-like Recombination Proteins in Eukaryotes: Functions and Structures of RAD51 Genes T. Ogawa, A. Shinohara, A. Nabetani, T. Ikeya, X. Yu, E.H. Egelman, and H. Ogawa 567 Characterization of Sequences Responsible for trans-Inactivation of the Drosophila brown Gene L.E. Martin-Morris, K. Loughney, E.O. Kershisnik, G. Poortinga, and S. Henikoff 577 Position Effect Variegation and Genomic Instability A.C. Spradling 585 Mismatch Repair and Genetic Stability in Human Cells W.-H. Fang, G.-M. Li, M. Longley, J. Holmes, W. Thilly, and P. Modrich 597 Excision Repair in Man and the Molecular Basis of Xeroderma Pigmentosum Syndrome J.T. Reardon, L.H. Thompson, and A. Sancar 605 DNA Joining in Mammalian Cells T. Lindahl, C. Prigent, D.E. Barnes, A.R. Lehmann, M.S. Satoh, E. Roberts, R.A. Nash, P. Robins, and G. Daly 619 Nucleotide Excision Repair of DNA by Mammalian Cell Extracts and Purified Proteins R.D. Wood, A. Aboussekhra, M. Biggerstaff, C.J. Jones, A. O'Donovan, M.K.K. Shivji, and D.E. Szymkowski 625 Chromosomal Fragile Sites: Molecular Test of the Delayed-replication Model C.D. Laird, R.S. Hansen, T.K. Canfield, M.M. Lamb, and S.M. Gartler 633 Coupling DNA Replication to the Cell Cycle T.J. Kelly, P. Nurse, and S.L. Forsburg 637 Loss of Chromosomal Integrity in Neoplasia T.D. Tlsty, P. Jonczyk, A. White, M. Sage, L Hall, D. Schaefer, A. Briot, E. Livanos, H. Roelofs, B. Poulose, and J. Sanchez 645 xxiv CONTENTS

Ceil Cycle Regulation of Gene Amplification A. Di Leonardo, S.P. Linke, Y. Yin, and G.M. Wahl 655

Centromeres and Telomeres Molecular Analysis of the Budding Yeast Centromere/Kinetochore W. Jiang and J. Carbon 669 Structure and Function of Chromosomes in Mitosis of Budding Yeast V. Guacci, A. Yamamoto, A. Strunnikov, J. Kingsbury, E. Hogan, P. Meluh, and D. Koshland 677 Structure and Function of Schizosaccharomyces pombe Centromeres L. Clarke, M. Baum, L.G. Marschall, V.K. Ngan, and N.C. Steiner 687 The INCENPs: Structural and Functional Analysis of a Family of Chromosome Passenger Proteins A.M. Mackay and W.C. Earnshaw 697 In Vivo and In Vitro Studies of Telomeres and Telomerase M.S. Lee, R.C. Gallagher, J. Bradley, and E.H. Blackburn 707 Telomerase and Telomere-length Regulation: Lessons from Small Eukaryotes to Mammals C. W. Greider 719 Structural and Temporal Analysis of Telomere Replication in Yeast R.J. Wellinger, A.J. Wolf, and V.A. Zakian 725 The Positioning of Yeast Telomeres Depends on SIR3, SIR4, and the Integrity of the Nuclear Membrane F. Palladino, T. Laroche, E. Gilson, L. Pillus, and S.M. Gasser 733

Nuclear Structure Snurposomes and Coiled Bodies Z. Wu, C. Murphy, C.-H.H. Wu, A. Tsvetkov, and J. G. Gall 747 From the Chromosomal Loops and the Scaffold to the Classic Bands of Metaphase Chromosomes Y. Saitoh and U.K. Laemmli 755 Studies of Metaphase and Interphase Chromosomes Using Fluorescence In Situ Hybridization B.J. Trask, S. Allen, H. Massa, A. Fertitta, R. Sachs, G. van den Engh, and M. Wu 767 Role of Chromosome Territories in the Functional Compartmentalization of the Cell Nucleus T. Cremer, A. Kurz, R. Zirbel, S. Dietzel, B. Rinke, E. Schrdck, M.R. Speicher, U. Mathieu, A. Jauch, P. Emmerich, H. Scherthan, T. Ried, C. Cremer, and P. Lichter 777 Mechanisms of Intracellular Transcript Localization and Export in Early Drosophila Embryos I. Davis, H. Francis-Lang, and D. Ish-Horowicz 793 Dynamics of Transcription and Pre-mRNA Splicing within the Mammalian Cell Nucleus D.L. Spector, R.T. O'Keefe, and L.F. JimOnez-Garcla 799 Probing Functional Organization within the Nucleus: Is Genome Structure Integrated with RNA Metabolism? J.B. Lawrence, K.C. Carter, and X. Xing 807

Summary: Genetic Tinkering--Local Problems, Local Solutions H. Weintraub 819

Author Index 837

Subject Index 839