Genomes and Genes
Summary: Recombinases involved in the rearrangement of immunity-related GENES such as IMMUNOGLOBULIN GENES and T-CELL RECEPTOR GENES.
- Messier T, O Neill J, Hou S, Nicklas J, Finette B. In vivo transposition mediated by V(D)J recombinase in human T lymphocytes. EMBO J. 2003;22:1381-8 pubmed..These findings implicate V(D)J recombinase-mediated transposition as a mutagenic mechanism capable of deleterious genetic rearrangements in humans. ..
- Lee A, Fugmann S, Cowell L, Ptaszek L, Kelsoe G, Schatz D. A functional analysis of the spacer of V(D)J recombination signal sequences. PLoS Biol. 2003;1:E1 pubmed..quot; The interplay between such binary and multiplicative modes of interactions provides a general model for analyzing protein-DNA interactions in various biological systems. ..
- Messier T, O Neill J, Finette B. V(D)J recombinase mediated inter-chromosomal HPRT alterations at cryptic recombination signal sequences in peripheral human T cells. Hum Mutat. 2006;27:829 pubmed
- Swanson P. The bounty of RAGs: recombination signal complexes and reaction outcomes. Immunol Rev. 2004;200:90-114 pubmed..Finally, I discuss alternative DNA transactions mediated by the V(D)J recombinase, the protein-DNA complexes that support them, and factors and forces that control them. ..
- Matthews A, Oettinger M. RAG: a recombinase diversified. Nat Immunol. 2009;10:817-21 pubmed publisher..Here we discuss some of these functions and suggest that the RAG-1-RAG-2 complex nucleates a specialized subnuclear compartment that we call the 'V(D)J recombination factory'. ..
- Liang H, Hsu L, Cado D, Cowell L, Kelsoe G, Schlissel M. The "dispensable" portion of RAG2 is necessary for efficient V-to-DJ rearrangement during B and T cell development. Immunity. 2002;17:639-51 pubmed
- Roth D. Restraining the V(D)J recombinase. Nat Rev Immunol. 2003;3:656-66 pubmed..What mechanisms constrain the dangerous potential of the recombinase and preserve genomic integrity during immune-system development? ..
- Landree M, Wibbenmeyer J, Roth D. Mutational analysis of RAG1 and RAG2 identifies three catalytic amino acids in RAG1 critical for both cleavage steps of V(D)J recombination. Genes Dev. 1999;13:3059-69 pubmed..These data suggest that RAG-mediated DNA cleavage involves coordination of divalent metal ion(s) by RAG1. ..
- Cannon J, Haire R, Rast J, Litman G. The phylogenetic origins of the antigen-binding receptors and somatic diversification mechanisms. Immunol Rev. 2004;200:12-22 pubmed..Such studies have the potential for uncovering previously unknown mechanisms of generating receptor diversity. ..
- Ramsden D, Gellert M. Formation and resolution of double-strand break intermediates in V(D)J rearrangement. Genes Dev. 1995;9:2409-20 pubmed..Efficient formation of signal junctions may require cell cycle progression, or down-regulation of the recombination machinery. ..
- Raghavan S, Kirsch I, Lieber M. Analysis of the V(D)J recombination efficiency at lymphoid chromosomal translocation breakpoints. J Biol Chem. 2001;276:29126-33 pubmed..These results quantify one of the three major factors that determine the frequency of these translocations in T-cell acute lymphocytic leukemia. ..
- Pelanda R, Braun U, Hobeika E, Nussenzweig M, Reth M. B cell progenitors are arrested in maturation but have intact VDJ recombination in the absence of Ig-alpha and Ig-beta. J Immunol. 2002;169:865-72 pubmed..Finally, Ig-alpha and Ig-beta are not redundant in their putative function, as pro-B cells from Ig-alpha and Ig-beta double-deficient mice are similar to those from single-deficient animals in every aspect analyzed. ..
- Sollbach A, Wu G. Inversions produced during V(D)J rearrangement at IgH, the immunoglobulin heavy-chain locus. Mol Cell Biol. 1995;15:671-81 pubmed..We suggest that inverted DJH rearrangements are influenced by V(D)J recombination mechanistic constraints and cellular selection. ..
- Olaru A, Patterson D, Villey I, Livak F. DNA-Rag protein interactions in the control of selective D gene utilization in the TCR beta locus. J Immunol. 2003;171:3605-11 pubmed
- Chatterji M, Tsai C, Schatz D. New concepts in the regulation of an ancient reaction: transposition by RAG1/RAG2. Immunol Rev. 2004;200:261-71 pubmed..A major challenge has been to determine how the transposition activity of the RAG proteins is regulated in vivo. Although a variety of mechanisms have been suggested by recent studies, a clear resolution of this issue remains elusive. ..
- Schatz D, Oettinger M, Baltimore D. The V(D)J recombination activating gene, RAG-1. Cell. 1989;59:1035-48 pubmed..RAG-1 may activate V(D)J recombination indirectly, or it may encode the V(D)J recombinase itself. ..
- Akamatsu Y, Monroe R, Dudley D, Elkin S, Gartner F, Talukder S, et al. Deletion of the RAG2 C terminus leads to impaired lymphoid development in mice. Proc Natl Acad Sci U S A. 2003;100:1209-14 pubmed..We discuss potential roles of the RAG2 C terminus in mediating rearrangement of endogenous antigen-receptor loci. ..
- Hesslein D, Pflugh D, Chowdhury D, Bothwell A, Sen R, Schatz D. Pax5 is required for recombination of transcribed, acetylated, 5' IgH V gene segments. Genes Dev. 2003;17:37-42 pubmed..The finding of transcribed, histone acetylated gene segments that fail to recombine suggests that a Pax5-dependent regulatory mechanism is required in addition to standard constraints of accessibility to control V(H) gene recombination. ..
- Rooney S, Sekiguchi J, Zhu C, Cheng H, Manis J, Whitlow S, et al. Leaky Scid phenotype associated with defective V(D)J coding end processing in Artemis-deficient mice. Mol Cell. 2002;10:1379-90 pubmed..Finally, Artemis deficiency leads to chromosomal instability in fibroblasts, demonstrating that Artemis functions as a genomic caretaker. ..
- Jones J, Gellert M. The taming of a transposon: V(D)J recombination and the immune system. Immunol Rev. 2004;200:233-48 pubmed..This work highlights the considerable diversity of transposition systems and their relation to V(D)J recombination. ..
- Han S, Zheng B, Schatz D, Spanopoulou E, Kelsoe G. Neoteny in lymphocytes: Rag1 and Rag2 expression in germinal center B cells. Science. 1996;274:2094-7 pubmed..Germinal center B cells thus share fundamental characteristics of immature lymphocytes, raising the possibility that antigen-dependent secondary V(D)J rearrangements modify the peripheral antibody repertoire. ..
- Qiu J, Kale S, Yarnell Schultz H, Roth D. Separation-of-function mutants reveal critical roles for RAG2 in both the cleavage and joining steps of V(D)J recombination. Mol Cell. 2001;7:77-87 pubmed..Moreover, the discovery that some mutants block RAG-mediated hairpin opening in vitro provides a critical link between this biochemical activity and coding joint formation in vivo. ..
- Bassing C, Swat W, Alt F. The mechanism and regulation of chromosomal V(D)J recombination. Cell. 2002;109 Suppl:S45-55 pubmed..We review our current understanding of the V(D)J recombination reaction and how it is regulated during lymphocyte development. We also discuss how defects in the mechanism or regulation of V(D)J recombination can lead to human disease. ..
- Wang X, Xiao G, Zhang Y, Wen X, Gao X, Okada S, et al. Regulation of Tcrb recombination ordering by c-Fos-dependent RAG deposition. Nat Immunol. 2008;9:794-801 pubmed publisher..Our results show an unexpected function for c-Fos as a direct regulator of Tcrb recombination, rather than its usual function as a transcription regulator, and provide new insight into the mechanisms of recombination ordering. ..
- Lu C, Posey J, Roth D. Understanding how the V(D)J recombinase catalyzes transesterification: distinctions between DNA cleavage and transposition. Nucleic Acids Res. 2008;36:2864-73 pubmed publisher..These findings provide the first identification of components of Rag1 that are specifically required for transesterification and suggest an unexpected role for Rag2 in DNA cleavage and transposition. ..
- Matthews A, Kuo A, Ramon Maiques S, Han S, Champagne K, Ivanov D, et al. RAG2 PHD finger couples histone H3 lysine 4 trimethylation with V(D)J recombination. Nature. 2007;450:1106-10 pubmed..Furthermore, our results provide the first evidence indicating that disrupting the read-out of histone modifications can cause an inherited human disease. ..
- Curry J, Geier J, Schlissel M. Single-strand recombination signal sequence nicks in vivo: evidence for a capture model of synapsis. Nat Immunol. 2005;6:1272-9 pubmed..These data support a model of capture rather than synapsis for pairwise RSS cleavage during V(D)J recombination. ..
- Lee G, Neiditch M, Salus S, Roth D. RAG proteins shepherd double-strand breaks to a specific pathway, suppressing error-prone repair, but RAG nicking initiates homologous recombination. Cell. 2004;117:171-84 pubmed..We also find that RAG-mediated nicks efficiently stimulate homologous recombination and discuss the implications of these findings for oncogenic chromosomal rearrangements, evolution, and gene targeting. ..
- Borghesi L, Hsu L, Miller J, Anderson M, Herzenberg L, Herzenberg L, et al. B lineage-specific regulation of V(D)J recombinase activity is established in common lymphoid progenitors. J Exp Med. 2004;199:491-502 pubmed..As activity of the Erag enhancer is restricted to the B cell lineage, this provides the first molecular evidence for establishment of a lineage-specific transcription program in multipotent progenitors. ..
- Dudley D, Sekiguchi J, Zhu C, Sadofsky M, Whitlow S, DeVido J, et al. Impaired V(D)J recombination and lymphocyte development in core RAG1-expressing mice. J Exp Med. 2003;198:1439-50 pubmed..We discuss the potential implications of these findings for noncore RAG1 functions and for the ordered assembly of VH, DH, and JH segments. ..
- Clatworthy A, Valencia M, Haber J, Oettinger M. V(D)J recombination and RAG-mediated transposition in yeast. Mol Cell. 2003;12:489-99 pubmed..Cleaved signal ends are also transposed into new sites in DNA, allowing RAG-induced transposition to be studied in vivo. ..
- Ross A, Vuica M, Desiderio S. Overlapping signals for protein degradation and nuclear localization define a role for intrinsic RAG-2 nuclear uptake in dividing cells. Mol Cell Biol. 2003;23:5308-19 pubmed..These results suggest that the intrinsic RAG-2 NLS functions in the nuclear uptake of RAG-2 following its reexpression in cycling cells. ..
- Barndt R, Dai M, Zhuang Y. Functions of E2A-HEB heterodimers in T-cell development revealed by a dominant negative mutation of HEB. Mol Cell Biol. 2000;20:6677-85 pubmed..These results indicate that E2A-HEB heterodimers play obligatory roles both before and after TCRbeta gene rearrangement during the alpha/beta lineage T-cell development. ..
- Kapitonov V, Jurka J. RAG1 core and V(D)J recombination signal sequences were derived from Transib transposons. PLoS Biol. 2005;3:e181 pubmed..We also suggest that the RAG2 protein was not encoded by ancient Transib transposons but emerged in jawed vertebrates as a counterpart of RAG1 necessary for the V(D)J recombination reaction...
- Roman C, Cherry S, Baltimore D. Complementation of V(D)J recombination deficiency in RAG-1(-/-) B cells reveals a requirement for novel elements in the N-terminus of RAG-1. Immunity. 1997;7:13-24 pubmed..Our data suggest that the RAG-1 N-terminus enhances the formation of an active recombination complex that facilitates the rearrangement process. ..
- Tillman R, Wooley A, Hughes M, Khor B, Sleckman B. Regulation of T-cell receptor beta-chain gene assembly by recombination signals: the beyond 12/23 restriction. Immunol Rev. 2004;200:36-43 pubmed..By preserving Dbeta gene segment utilization, the B12/23 restriction is required, at a minimum, for the generation of a diverse repertoire of TCRbeta chains. ..
- Grawunder U, Zimmer D, Fugmann S, Schwarz K, Lieber M. DNA ligase IV is essential for V(D)J recombination and DNA double-strand break repair in human precursor lymphocytes. Mol Cell. 1998;2:477-84 pubmed..Hence, DNA ligase IV is the activity responsible for the ligation step in NHEJ and in V(D)J recombination. ..
- Lee G, Neiditch M, Sinden R, Roth D. Targeted transposition by the V(D)J recombinase. Mol Cell Biol. 2002;22:2068-77 pubmed..The RAG proteins are capable of mediating all necessary breakage and joining events on both partner chromosomes; thus, the V(D)J recombinase may be far more culpable for oncogenic translocations than has been suspected. ..
- Fuxa M, Skok J, Souabni A, Salvagiotto G, Roldan E, Busslinger M. Pax5 induces V-to-DJ rearrangements and locus contraction of the immunoglobulin heavy-chain gene. Genes Dev. 2004;18:411-22 pubmed..Pax5 subsequently activates locus contraction and distal VH-DJH rearrangements in collaboration with an unknown factor that is present in pro-B cells, but absent in thymocytes. ..
- Kim D, Dai Y, Mundy C, Yang W, Oettinger M. Mutations of acidic residues in RAG1 define the active site of the V(D)J recombinase. Genes Dev. 1999;13:3070-80 pubmed..Our results support a model in which the RAG1 protein contains the active site of the V(D)J recombinase and are interpreted in light of predictions about the structure of RAG1. ..
- Corneo B, Moshous D, Gungor T, Wulffraat N, Philippet P, Le Deist F, et al. Identical mutations in RAG1 or RAG2 genes leading to defective V(D)J recombinase activity can cause either T-B-severe combined immune deficiency or Omenn syndrome. Blood. 2001;97:2772-6 pubmed..The nature of this factor is discussed. ..
- Whitehurst C, Schlissel M, Chen J. Deletion of germline promoter PD beta 1 from the TCR beta locus causes hypermethylation that impairs D beta 1 recombination by multiple mechanisms. Immunity. 2000;13:703-14 pubmed..These findings suggest that methylation can regulate V(D)J recombination both at a general level by influencing regional chromatin accessibility and specifically by blocking RSS recognition or cleavage by the V(D)J recombinase. ..
- West K, Singha N, De Ioannes P, Lacomis L, Erdjument Bromage H, Tempst P, et al. A direct interaction between the RAG2 C terminus and the core histones is required for efficient V(D)J recombination. Immunity. 2005;23:203-12 pubmed..Point mutations that disrupt the RAG2-histone association inhibit the efficiency of the V(D)J recombination reaction at the endogenous immunoglobulin locus, with the most dramatic effect in the V to DJ(H) rearrangement. ..
- Allman D, Li J, Hardy R. Commitment to the B lymphoid lineage occurs before DH-JH recombination. J Exp Med. 1999;189:735-40 pubmed
- Kumaki S, Villa A, Asada H, Kawai S, Ohashi Y, Takahashi M, et al. Identification of anti-herpes simplex virus antibody-producing B cells in a patient with an atypical RAG1 immunodeficiency. Blood. 2001;98:1464-8 pubmed
- Borghesi L, Gerstein R. Developmental separation of V(D)J recombinase expression and initiation of IgH recombination in B lineage progenitors in vivo. J Exp Med. 2004;199:483-9 pubmed..Our results indicate that the onset of recombinase activity and the initiation of IgH recombination are developmentally distinct events in the B lineage. ..
- Franco D, Chang Y. Accessibility of chromosomal recombination breaks in nuclei of wild-type and DNA-PKcs-deficient cells. DNA Repair (Amst). 2009;8:813-21 pubmed publisher..e., the greater the accessibility of the coding ends, the higher level of coding joints formed. Taken together, our findings provide important insights into the resolution of recombination ends by error-prone alternative NHEJ pathways. ..
- Schatz D. V(D)J recombination. Immunol Rev. 2004;200:5-11 pubmed
- Fugmann S, Villey I, Ptaszek L, Schatz D. Identification of two catalytic residues in RAG1 that define a single active site within the RAG1/RAG2 protein complex. Mol Cell. 2000;5:97-107 pubmed
- Dreyfus D. The DDE recombinases: diverse roles in acquired and innate immunity. Ann Allergy Asthma Immunol. 2006;97:567-76; quiz 576-8, 602 pubmed
- Cuomo C, Mundy C, Oettinger M. DNA sequence and structure requirements for cleavage of V(D)J recombination signal sequences. Mol Cell Biol. 1996;16:5683-90 pubmed..Sequence alterations that facilitate unpairing of the bases at the signal/coding border activate the cleavage reaction, suggesting that DNA distortion is critical for V(D)J recombination. ..
- Tsai C, Drejer A, Schatz D. Evidence of a critical architectural function for the RAG proteins in end processing, protection, and joining in V(D)J recombination. Genes Dev. 2002;16:1934-49 pubmed..Our results suggest that the RAG proteins have an architectural function in facilitating proper and efficient V(D)J joining, and a protective function in preventing degradation of broken ends prior to joining. ..
- Rahman N, Godderz L, Stray S, Capra J, Rodgers K. DNA cleavage of a cryptic recombination signal sequence by RAG1 and RAG2. Implications for partial V(H) gene replacement. J Biol Chem. 2006;281:12370-80 pubmed..These results have implications for further diversification of the antigen receptor repertoire as well as the role of the RAG proteins in genomic instability. ..
- Reddy Y, Perkins E, Ramsden D. Genomic instability due to V(D)J recombination-associated transposition. Genes Dev. 2006;20:1575-82 pubmed..In total, transposition occurred approximately once every 50,000 V(D)J recombinations. Transposition may thus contribute significantly to genomic instability. ..
- Hempel W, Stanhope Baker P, Mathieu N, Huang F, Schlissel M, Ferrier P. Enhancer control of V(D)J recombination at the TCRbeta locus: differential effects on DNA cleavage and joining. Genes Dev. 1998;12:2305-17 pubmed
- Livak F, Petrie H. Access roads for RAG-ged terrains: control of T cell receptor gene rearrangement at multiple levels. Semin Immunol. 2002;14:297-309 pubmed..The emerging results suggest that formation of the primary repertoire is controlled by two, partially independent factors: chromosomal accessibility and direct recombinase-DNA interactions. ..
- Jung D, Alt F. Unraveling V(D)J recombination; insights into gene regulation. Cell. 2004;116:299-311 pubmed
- Swanson P, Volkmer D, Wang L. Full-length RAG-2, and not full-length RAG-1, specifically suppresses RAG-mediated transposition but not hybrid joint formation or disintegration. J Biol Chem. 2004;279:4034-44 pubmed
- Arbuckle J, Fauss L, Simpson R, Ptaszek L, Rodgers K. Identification of two topologically independent domains in RAG1 and their role in macromolecular interactions relevant to V(D)J recombination. J Biol Chem. 2001;276:37093-101 pubmed..The C-terminal domain bound DNA cooperatively but did not show specificity for either conserved RSS element. This domain was also found to self-associate, implicating it as a dimerization domain within RAG1. ..
- Neiditch M, Lee G, Huye L, Brandt V, Roth D. The V(D)J recombinase efficiently cleaves and transposes signal joints. Mol Cell. 2002;9:871-8 pubmed
- Komori T, Okada A, Stewart V, Alt F. Lack of N regions in antigen receptor variable region genes of TdT-deficient lymphocytes. Science. 1993;261:1171-5 pubmed
- Oettinger M, Schatz D, Gorka C, Baltimore D. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science. 1990;248:1517-23 pubmed..RAG-1 and RAG-2 might activate the expression of the V(D)J recombinase but, more likely, they directly participate in the recombination reaction. ..
- Bailey S, Rosenberg N. Assessing the pathogenic potential of the V(D)J recombinase by interlocus immunoglobulin light-chain gene rearrangement. Mol Cell Biol. 1997;17:887-94 pubmed..Considering the large numbers of lymphocytes generated throughout life, aberrant rearrangements generated by the V(D)J recombinase may be relatively common...
- De P, Peak M, Rodgers K. DNA cleavage activity of the V(D)J recombination protein RAG1 is autoregulated. Mol Cell Biol. 2004;24:6850-60 pubmed..We propose how the combined actions of the RAG1 domains may function in V(D)J recombination and also in aberrant cleavage reactions that may lead to genomic instability in B and T lymphocytes. ..
- Nutt S, Urbanek P, Rolink A, Busslinger M. Essential functions of Pax5 (BSAP) in pro-B cell development: difference between fetal and adult B lymphopoiesis and reduced V-to-DJ recombination at the IgH locus. Genes Dev. 1997;11:476-91 pubmed..In contrast, V(H)-to-D(H)J(H) rearrangements were reduced approximately 50-fold in Pax5-deficient pre-BI cells, suggesting a role for Pax5 in the developmental pathway controlling V-to-DJ recombination. ..
- Olaru A, Patterson D, Cai H, Livak F. Recombination signal sequence variations and the mechanism of patterned T-cell receptor-beta locus rearrangement. Mol Immunol. 2004;40:1189-201 pubmed
- Goebel P, Janney N, Valenzuela J, Romanow W, Murre C, Feeney A. Localized gene-specific induction of accessibility to V(D)J recombination induced by E2A and early B cell factor in nonlymphoid cells. J Exp Med. 2001;194:645-56 pubmed..We propose that accessibility occurs in a local manner, and that binding sites for factors facilitating accessibility are therefore likely to be associated with individual gene segments. ..
- Morshead K, Ciccone D, Taverna S, Allis C, Oettinger M. Antigen receptor loci poised for V(D)J rearrangement are broadly associated with BRG1 and flanked by peaks of histone H3 dimethylated at lysine 4. Proc Natl Acad Sci U S A. 2003;100:11577-82 pubmed..The specific patterns of modification imply that the regulation of V(D)J recombination involves recruitment of specific methyltransferases in a localized manner. ..
- Jones J, Gellert M. Ordered assembly of the V(D)J synaptic complex ensures accurate recombination. EMBO J. 2002;21:4162-71 pubmed..Additional cellular factors such as chromatin may ensure that RAG1/2 first assembles on a 12 RSS, and then a free 23 RSS enters to activate cleavage. ..
- Lieber M, Ma Y, Pannicke U, Schwarz K. The mechanism of vertebrate nonhomologous DNA end joining and its role in V(D)J recombination. DNA Repair (Amst). 2004;3:817-26 pubmed..The NHEJ pathway is needed to repair these physiologic breaks, as well as challenging pathologic breaks that arise from ionizing radiation and oxidative damage to DNA. ..
- Bories J, Demengeot J, Davidson L, Alt F. Gene-targeted deletion and replacement mutations of the T-cell receptor beta-chain enhancer: the role of enhancer elements in controlling V(D)J recombination accessibility. Proc Natl Acad Sci U S A. 1996;93:7871-6 pubmed..These results demonstrate a critical role for Ebeta in promoting accessibility of the TCRbeta locus and suggest that additional negative elements may cooperate to further modulate this process. ..
- Cobb R, Oestreich K, Osipovich O, Oltz E. Accessibility control of V(D)J recombination. Adv Immunol. 2006;91:45-109 pubmed..The discussion will focus on cis-acting regulation by ACEs, the nuclear factors that control ACE function, and the epigenetic modifications that establish recombinase accessibility. ..
- Nagawa F, Hirose S, Nishizumi H, Nishihara T, Sakano H. Joining mutants of RAG1 and RAG2 that demonstrate impaired interactions with the coding-end DNA. J Biol Chem. 2004;279:38360-8 pubmed..A possible role of this RAG coding region interaction is discussed in the context of V(D)J recombination. ..
- Perkins E, Nair A, Cowley D, van Dyke T, Chang Y, Ramsden D. Sensing of intermediates in V(D)J recombination by ATM. Genes Dev. 2002;16:159-64 pubmed..We suggest routine surveillance of intermediates in V(D)J recombination by ATM helps suppress potentially oncogenic translocations when repair fails. ..
- Peak M, Arbuckle J, Rodgers K. The central domain of core RAG1 preferentially recognizes single-stranded recombination signal sequence heptamer. J Biol Chem. 2003;278:18235-40 pubmed..This study provides important insight into the V(D)J recombination reaction, specifically that significant interaction of the RSS heptamer with RAG1 occurs only after the induction of conformational changes at the RSS heptamer. ..