Advances in Immunology [Vol 94] [AID for Immunoglobulin Diversity] - F. Alt, T. Honjo (AP, 2007) WW

327 Pages·2007·3.69 MB·English

Associate Editors

K. Frank Austen

Division of Rheumatology
Immunology & Allergy
Harvard Medical School, Boston, Massachusetts

Tasuku Honjo

Graduate School of Medicine and
Faculty of Medicine, Kyoto University
Kyoto, Japan

Fritz Melchers

Department of Cell Biology
University of Basel
Basel, Switzerland

Jonathan W. Uhr

Department of Microbiology &
Internal Medicine
University of Texas, Dallas, Texas

Emil R. Unanue

Department of Pathology & Immunology
Washington University
St. Louis, Missouri

Contributors

Numbers in parentheses indicate the pages on which the authors’ contributions begin.

Frederick W. Alt (157), The Howard Hughes Medical Institute, The
Children’s Hospital, The CBR Institute for Biomedical Research and
Department of Genetics, Harvard Medical School, Boston, Massachusetts
Vasco Barreto (75), Laboratory of Molecular Immunology, The Rockefeller
University, New York, New York
Uttiya Basu (157), The Howard Hughes Medical Institute, The Children’s
Hospital, The CBR Institute for Biomedical Research and Department of
Genetics, Harvard Medical School, Boston, Massachusetts
Nasim A. Begum (1), Department of Immunology and Genomic Medicine
and 21 Century COE Formation, Graduate School of Medicine, Kyoto
University, Kyoto, Japan
Jayanta Chaudhuri (157), Immunology Program, Memorial Sloan Kettering
Cancer Center, New York, New York
Silvestro G. Conticello (37), Medical Research Council Laboratory of
Molecular Biology, Cambridge CB2 2QH, United Kingdom
Abhishek Datta (157), The Howard Hughes Medical Institute, The
Children’s Hospital, The CBR Institute for Biomedical Research and
Department of Genetics, Harvard Medical School, Boston, Massachusetts
Anne Durandy (275), Inserm, U768, Paris F-75015, France; Univ Rene´
Descartes-Paris 5, F-75006, France; Assistance Publique Hoˆpitaux de Paris,
Hoˆpital Necker-Enfants Malades, 149 rue de Se`vres 75015 Paris, France
Alain Fischer (275), Inserm, U768, Paris F-75015, France; Univ Rene´
Descartes-Paris 5, F-75006, France; Assistance Publique Hoˆpitaux de Paris
and Unite´ d’immunologie et He´matologie Pe´diatrique, Hoˆpital Necker-
Enfants Malades, 149 rue de Se`vres 75015 Paris, France
Sonia Franco (157), The Howard Hughes Medical Institute, The Children’s
Hospital, The CBR Institute for Biomedical Research and Department of
Genetics, Harvard Medical School, Boston, Massachusetts

ix

Myron F. Goodman (127), Department of Biological Sciences and
Department of Chemistry, University of Southern California, Los
Angeles, California
Tasuku Honjo (1, 245), Department of Immunology and Genomic Medicine,
Graduate School of Medicine, Kyoto University, Kyoto, Japan
Mila Jankovic (75), Laboratory of Molecular Immunology, The Rockefeller
University, New York, New York
Ai Kotani (245), Department of Immunology and Genomic Medicine,
Graduate School of Medicine, Kyoto University, Kyoto, Japan
Marc-Andre Langlois (37), Medical Research Council Laboratory of
Molecular Biology, Cambridge CB2 2QH, United Kingdom
John Manis (157), Joint Program in Transfusin Medicine, Department of
Pathology, Children’s Hospital, Harvard Medical School, Boston,
Massachusetts
Kevin McBride (75), Laboratory of Molecular Immunology, The Rockefeller
University, New York, New York
Masamichi Muramatsu (1), Department of Immunology and Genomic
Medicine and 21 Century COE Formation, Graduate School of Medicine,
Kyoto University, Kyoto, Japan
Hitoshi Nagaoka (1), Department of Immunology and Genomic Medicine,
Graduate School of Medicine, Kyoto University, Kyoto, Japan
Michael S. Neuberger (37), Medical Research Council Laboratory of
Molecular Biology, Cambridge CB2 2QH, United Kingdom
Andre´ Nussenzweig (75), Experimental Immunology Branch, National
Cancer Institute, National Institutes of Health, Bethesda, Maryland
Michel C. Nussenzweig (75), Laboratory of Molecular Immunology, The
Rockefeller University, New York, New York; Howard Hughes Medical
Institute, Maryland
Il-mi Okazaki (245), Department of Immunology and Genomic Medicine,
Graduate School of Medicine, Kyoto University, Kyoto, Japan
F. Nina Papavasiliou (215), Laboratory of Lymphocyte Biology, The
Rockefeller University, New York, New York
Thomas Perlot (157), The Howard Hughes Medical Institute, The Children’s
Hospital, The CBR Institute for Biomedical Research and Department of
Genetics, Harvard Medical School, Boston, Massachusetts
Sophie Peron (275), Inserm, U768, Paris F-75015, France; Univ Rene´
Descartes-Paris 5, Paris F-75006, France; Hoˆpital Necker-Enfants Malades,
149 rue de Se`vres 75015 Paris, France
Ryan T. Phan (157), The Howard Hughes Medical Institute, The Children’s
Hospital, The CBR Institute for Biomedical Research and Department of
Genetics, Harvard Medical School, Boston, Massachusetts

x
contributors

Almudena Ramiro (75), DNA Hypermutation and Cancer Group, Spanish
National Cancer Center (CNIO), Melchor Fernandez Almagro, 3,
28029 Madrid, Spain
Bernardo Reina San-Martin (75), Institut de Ge´ne´tique et de Biologie
Mole´culaire et Cellulaire, De´partement de, Pathologie Mole´culaire, 1 rue
Laurent Fries, 67404 Illkirch CEDEX, France
Floyd E. Romesberg (127), Department of Chemistry, The Scripps Research
Institute, La Jolla, California
Brad R. Rosenberg (215), Laboratory of Lymphocyte Biology, The
Rockefeller University, New York, New York
Matthew D. Scharff (127), Department of Cell Biology, Albert Einstein
College of Medicine, Bronx, New York
David G. Schatz (109), Section of Immunology and Howard Hughes Medical
Institute, Yale University School of Medicine, New Haven, Connecticut
Reiko Shinkura (1), Department of Immunology and Genomic Medicine,
Graduate School of Medicine, Kyoto University, Kyoto, Japan
Nadine Taubenheim (275), Inserm, U768, Paris F-75015, France; Univ
Rene´ Descartes-Paris 5, Paris F-75006, France; Hoˆpital Necker-Enfants
Malades, 149 rue de Se`vres 75015 Paris, France
Bao Vuong (157), Immunology Program, Memorial Sloan Kettering Cancer
Center, New York, New York
Jing Wang (157), The Howard Hughes Medical Institute, The Children’s
Hospital, The CBR Institute for Biomedical Research and Department of
Genetics, Harvard Medical School, Boston, Massachusetts
Catherine Yan (157), The Howard Hughes Medical Institute, The Children’s
Hospital, The CBR Institute for Biomedical Research and Department of
Genetics, Harvard Medical School, Boston, Massachusetts
Shu Yuan Yang (109), Section of Immunobiology, Yale University School of
Medicine, New Haven, Connecticut
Zizhen Yang (37), Medical Research Council Laboratory of Molecular
Biology, Cambridge CB2 2QH, United Kingdom
Ali Zarrin (157), The Howard Hughes Medical Institute, The Children’s
Hospital, The CBR Institute for Biomedical Research and Department of
Genetics, Harvard Medical School, Boston, Massachusetts

contributors
xi

Preface

This volume covers the exciting advances that have been made in our under-
standing of the generation of antibody diversity subsequent to the discovery of
the activation‐induced cytidine deaminase (AID). In this regard, the volume is
organized into nine separate chapters, most of which focus on particular
aspects of AID and the immunoglobulin gene diversification processes in
which it functions. This short introductory overview summarizes some of the
most relevant topics and points to particular chapters in which specific topics
are covered. However, the reader is encouraged to go through all of the
chapters to gain a complete understanding of this fascinating area of biology.
In that regard, while individual chapters tend to focus on particular topics, they
necessarily cover overlapping subject matter but often, given that this is still a
developing field, from different viewpoints.
The AID protein is necessary and sufficient for the initiation of immunoglo-
bluin heavy chain class switch recombination (CSR) and the initiation of somatic
hypermutation (SHM) of immunoglobulin variable region exons. That one
enzyme can induce the seemingly very different CSR and SHM mechanisms,
and that this enzyme can also induce the process of gene conversion in chickens,
was a very remarkable and unexpected finding. Moreover, the mechanism of
SHM was considered by many as one of the last major frontiers of immunology,
until the discovery that AID is the long sought mutator. Thus, the discovery of
AID, about 7 years ago, revolutionized our understanding of the peripheral
mechanism of immunoglobulin gene diversification and led to a huge body of
additional work. The work that led to the discovery of AID is discussed in depth
in Chapte r 1 by M uramatsu et al. An in‐ depth rev iew of CSR is presen ted in
Chapte r 6 by Chaudh uri et al . and a detailed in troduction to SHM is prese nted
in Chapte r 4 by Yua n and Sc hatz.
AID is comprised of less than 200‐amino acid residues and carries a cytidine
deaminase motif. AID clearly is required to introduce DNA lesions into
variable region exons and switch regions during SHM and CSR, respectively.
However, many important questions remain concerning how AID leads to DNA
cleavage. A long-debated question is the nature of the direct target of cytidine
deamination in vivo by AID, DNA or RNA. AID is structurally related to
APOBEC1, which is an RNA editing enzyme. However, biochemical studies

xiii

have shown that purified AID deaminates cytidines on single‐strand DNA.
Considerations relevant to DNA versus RNA models for AID activity are
presented in depth in Chap ter 1 by Muramatsu et al. and in Chap ter 6 by
Chaudhuri et al.
There are many other important questions regarding the function and regula-
tion of AID. A key question is how AID‐initiated lesions lead to mutation of
variable region DNA and DNA double strand breaks within switch regions. In
this context, another major question is the identification of modifications or co-
factors that might influence AID activity and potentially channel AID functions
into SHM or CSR. An extremely important question is the nature of the mechan-
isms that normally target the activities of this potent mutator to immunoglobulin
genes and not other genes. These general topics are discussed in Chapter 1 by
Muramatsu et a l., in Chapter 3 by Ramiro et a l., and in Chapter 6 by Chaudhuri
et al . AID biochemistry is a particular focus of Chapter 5 by Goodman et a l. while
issues related to AID targeting are a focus of Chapter 4 by Yuan and Schatz, which
also describes gene conversion.
The nature of the mechanisms that join AID‐initiated breaks in the context
of CSR has been a major area of study. Several studies have shown that general
DNA double strand break repair mechanisms are harnessed to join AID‐
dependent breaks in switch regions. This topic is a particular focus of
Chapter 3 by Ramir o et al . and is also covered in depth in Chapte r 6 by
Chaudhuri et al. AID also has been demonstrated to be involved in the
initiation of translocations that arise in the context of IgH CSR, including
oncogeni c transloc ations found in certain B ‐ce ll lymph omas. Chapter 3 also
discusses this topic in depth. Transgenic studies have further indicated that
AID expression can lead to other types of tumors, raising the question of how
broadly AID might function to generate certain forms of human cancer. This
topic is discusse d in Chapte r 8 by Ok azaki et al .
AID deficiency causes a severe immune deficiency in humans that is called
hyper IgM syndrome type II. This disease causes the absence of IgH isotypes
other than IgM and absence of hypermutation and, thereby, results in severe
susceptibility to bacterial infection. As there are other forms of hyper IgM
type II not yet fully characterized, the question arises whether further studies
of these deficiencies may reveal other functions for AID or potential cofactors.
The pathophy siology of AID deficien cy in huma ns is the subjec t of Chapter 9 by
Durandy et al.
Finally, an important question is whether AID might have functions beyond
somatic mutation and CSR. This possibility is supported by findings that
molecules related to AID in HIV resistance and that AID is induced after

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PREFACE

infection by various viruses. This exciting new area of investigation is covered
in Chapter 2 by Contic ello et al . and in Chapte r 7 by R osenberg and
Papavasiliou.

Frederick W. Alt
Tasuku Honjo

PREFACE
xv

Contents

Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ix
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
xiii

Discovery of Activation-Induced Cytidine Deaminase,
the Engraver of Antibody Memory

Masamichi Muramatsu, Hitoshi Nagaoka, Reiko Shinkura,
Nasim A. Begum, and Tasuku Honjo

Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
2. Identification of AID as a Key Molecule
in CSR and SHM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4
3. AID Is the Only B-Cell-Specific Factor Required for
Both CSR and SHM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
4. Functional Domains of AID . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
5. AID Is Involved in a DNA Cleavage Step. . . . . . . . . . . . . . . . . . . .
14
6. Major Hypotheses for the Action of AID . . . . . . . . . . . . . . . . . . . .
16
7. Critical Examination of the DNA Deamination Model. . . . . . . . . .
19
8. Evidence for a Novel Function of UNG in CSR . . . . . . . . . . . . . .
24
9. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29

DNA Deamination in Immunity: AID in the
Context of Its APOBEC Relatives

Silvestro G. Conticello, Marc-Andre Langlois,
Zizhen Yang, and Michael S. Neuberger

Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
37
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
38

v

2. AID: The DNA Deaminase Trigger for
Antibody Diversification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
38
3. The Zn-Dependent Deaminase Superfamily . . . . . . . . . . . . . . . . . .
39
4. Timeline of AID/APOBEC Evolution . . . . . . . . . . . . . . . . . . . . . . .
48
5. APOBEC1: An RNA-Editing Enzyme That Can Also
Act on DNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
49
6. APOBEC2: A Muscle-Specific Family Member of Unknown
Function/Activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
50
7. APOBEC4: A Distant or Ancestral Member of
the AID/APOBEC Family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
51
8. APOBEC3s: DNA Deaminases Active
in Viral Restriction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
52
9. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
63
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
63

The Role of Activation-Induced Deaminase in Antibody
Diversification and Chromosome Translocations

Almudena Ramiro, Bernardo Reina San-Martin, Kevin McBride,
Mila Jankovic, Vasco Barreto, Andre´ Nussenzweig, and
Michel C. Nussenzweig

Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
75
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
76
2. Events Preceding the DNA Lesion . . . . . . . . . . . . . . . . . . . . . . . . .
77
3. The DNA Lesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
78
4. DNA Damage Detection and Resolution During CSR . . . . . . . . . .
85
5. AID and Lymphomagenic Lesions. . . . . . . . . . . . . . . . . . . . . . . . . .
93
6. Conclusions and Perspectives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
96
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
96

Targeting of AID-Mediated Sequence Diversification
by cis-Acting Determinants

Shu Yuan Yang and David G. Schatz

Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
109
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
109
2. The Link Between Transcription and AID-Mediated
Sequence Diversification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
111
3. Other cis-Acting Determinants Involved in
the Targeting of AID . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
116

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contents