V(D)J Recombination

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.

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