V(d)J Recombination

ISBN-13: 9781493901241 / Angielski / Miękka / 2014 / 199 str.

Pierre Ferrier

Opis

v(D)J recombination: for the community of immunologists and developmental biologists, the molecular route by which B and T lymphocytes acquire their unique function of affording adaptive immunity. Yet, for many-from experienced scientists to trainees-it represents a (rather too) sophisticated process whose true insight is excessively demanding. However, when not simplyconsidered as a private ground for a few aficionados, it can be seen as a way of understanding how maturelympho cytes carry on their basic functions. For the group of aficionados-which includes this editor-it is an elegant paradigm featuring many fascinating evolutionary achievements of which the biological world alone has the secret. These include a subtle biochemical principle most likelyhijacked some 470 million years ago from an ancestral gene invader and since then cleverly adapted by jawed vertebrates to precisely cleave and rearrange their antigen receptor (Ig andTCR)loci. This invader would itself have assigned the services of the nonhomologous end joining (NHEJ) DNArepair machinery as well as various DNApolymerases or transferases to work in concert with developmental clues in lymphoid cell lineages to generate an immune repertoire and efficient host surveillance while avoiding autoimmunity. Recently, important new refinements in these systems have emerged, continuing to challenge ourknowledge andbeliefs. These arejust thetopics covered by the senior authors-all established leaders in this field-and their colleagues, whilst writing the various chapters in V(D)J Recombination."

Spis treści

1. Early Steps of V(D)J Rearangement: Insights from Biochemical Studies of RAG-RSS Complexes..... 1 Patrick C. Swanson, Sushil Kumar and Prafulla Raval Abstract..... 1 Introduction..... 1 Assembly and Organization of Single Site and Synaptic RAG-RSS Complexes..... 3 Insights into RAG-Mediated RSS Recognition and Cleavage Mechanisms..... 5 Elements Guiding Enforcement of the 12/23 Rule..... 8 Transcription Factor-Assisted Targeting of Antigen Receptor Loci..... 10 Conclusions and Future Directions..... 11 2. Regulation of RAG Transposition..... 16 Adam G.W. Matthews and Marjorie A. Oettinger Abstract..... 16 Introduction..... 16 Biochemistry of V(D)J Recombination..... 16 Overview of RAG Transposition..... 19 Regulation of RAG Transposition..... 24 Current Understanding of how RAG Transposition is Regulated..... 24 Additional Potential Regulatory Mechanisms..... 25 Summary..... 27 3. Recent Insights into the Formation of RAG-Induced Chromosomal Translocations..... 32 Vicky L. Brandt and David B. Roth Abstract..... 32 Introduction..... 32 Overview of the V(D)J Recombination Reaction..... 33 Potential Mechanisms of RAG-Mediated Translocations..... 34 Mistaken Identities: Substrate Selection Errors..... 34 The Ends that Got Away: Errors in Joining..... 36 4. V(D)J Recombination Deficiencies..... 46 Jean-Pierre de Villartay Abstract..... 46 Introduction..... 46 RAG1 and RAG2 Deficiencies..... 47 T-B-SCID with Radiosensitivity..... 50 5. Large-Scale Chromatin Remodeling at the Immunoglobulin Heav y Chain Locus: A Paradigm for Multigene Regulation..... 59 Daniel J. Bolland, Andrew L. Wood and Anne E. Corcoran Abstract..... 59 Introduction..... 60 Chromatin Remodeling..... 62 Intergenic Transcription..... 63 Intergenic Transcription in the Mouse Igh Locus V Region..... 63 Antisense Transcription..... 64 Antisense Transcription in the Igh Locus V Region..... 64 Antisense and Intergenic Transcription in the Igh D Region..... 66 Subnuclear Relocalisation..... 66 3-Dimensional Alterations in Chromatin Structure..... 67 Transcription Factories..... 68 Biased Recombination Frequency Explainedby Numerous Mechanisms..... 68 Allelic Choice and Allelic Exclusion..... 68 Other Antigen Receptor Loci..... 69 Future Directions..... 69 6. Genetic and Epigenetic Control of V Gene Rearangement Frequency..... 73 Ann J. Feeney Abstract..... 73 Introduction..... 73 Sequence Variation in RSS Can Greatly Affect Recombination..... 74 RSS Is Not Always Responsible for Unequal Rearrangement.....75 Chromatin as the Gatekeeper of Accessibility..... 75 Role of Transcription Factors in Controlling Rearrangement..... 77 Conclusions..... 79 7. Dynamic aspects of TCRa gene recombination: qualitative and quantitative assessments of the TCRa chain repertoire in Man and mouse..... 82 Evelyne Jouvin-Marche, Patrizia Fuschiotti and Patrice Noël Marche Abstract..... 82 Introduction..... 82 Complexity of mouse and human TCRAD locus..... 83 Analysis of human and mouse TCRA-chain diversity..... 84 Comparison between the frequencies of rearrangements in thymus and peripheral T-lymphocytes..... 85 The size of the mouse and human TCRa repertoire..... 87 Conclusion..... 90 8. Germline Transcription: A Key Regulator of Accessibility and Recombination..... 93 Iratxe Abarrategui and Michael S. Krangel Abstract..... 93 Introduction..... 93 A Brief History of Germline Transcription and

O autorze

PIERRE FERRIER is a Principal Investigator and Research Director at the

Centre d’Immunologie de Marseille-Luminy (CIML), France. He has also worked

as a Director of Marseille-Nice Genopole, a local consortium of more than twenty

laboratories aimed at developing high-throughput research techniques in genomics.

Main research interests include the analysis of the molecular mechanisms responsible

for the control of gene expression and recombination programs during hematopoietic

cell development and pathogenesis. He is a member of several national and international

scientific organizations including the Institut National de la Santé et de la

Recherche Médicale (Inserm), the Agence Nationale de la Recherche (ANR), the

Association pour la Recherche sur le Cancer (ARC), the Human Frontier Science

Program Organization (HFSPO), and the Université Virtuelle Médicale de Monaco

(UVMM). Pierre Ferrier received his academic degrees from Montpellier (MD) and

Marseille (PhD) Universities, France. He was a post-doctoral fellow (1986-90) in

the laboratory of Prof. F.W. Alt at the Columbia University College of Physicians

and Surgeons, New York, NY, USA.