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V(D)J Recombination: Mechanism, Errors, and Fidelity

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  • Author: David B. Roth1
  • Editors: Martin Gellert2, Nancy Craig3
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Pathology and Laboratory Medicine and the Center for Personalized Diagnostics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania 19104; 2: National Institutes of Health, Bethesda, MD; 3: Johns Hopkins University, Baltimore, MD
  • Source: microbiolspec November 2014 vol. 2 no. 6 doi:10.1128/microbiolspec.MDNA3-0041-2014
  • Received 09 July 2014 Accepted 15 July 2014 Published 21 November 2014
  • David Roth, david.roth2@uphs.upenn.edu
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  • Abstract:

    V(D)J recombination, the mechanism responsible for generating antigen receptor diversity, has the potential to generate aberrant DNA rearrangements in developing lymphocytes. Indeed, the recombinase has been implicated in several different kinds of errors leading to oncogenic transformation. Here we review the basic aspects of V(D)J recombination, mechanisms underlying aberrant DNA rearrangements, and the types of aberrant events uncovered in recent genomewide analyses of lymphoid neoplasms.

  • Citation: Roth D. 2014. V(D)J Recombination: Mechanism, Errors, and Fidelity. Microbiol Spectrum 2(6):MDNA3-0041-2014. doi:10.1128/microbiolspec.MDNA3-0041-2014.

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References

1. Brandt VL, Roth DB. 2008. G.O.D.'s Holy Grail: discovery of the RAG proteins. J Immunol 180:3:m. [PubMed][CrossRef]
2. Hozumi N, Tonegawa S. 1976. Evidence for somatic rearrangement of immunoglobulin genes coding for variable and constant regions. Proc Natl Acad Sci U S A 73:362862632. [CrossRef]
3. Onozawa M, Aplan PD. 2012. Illegitimate V(D)J recombination involving nonantigen receptor loci in lymphoid malignancy. Genes Chromosomes Cancer 51:5252n35.
4. Tsujimoto Y, Gorham J, Cossman J, Jaffe E, Croce CM. 1985. The t(14;18) chromosome translocations involved in B-cell neoplasms result from mistakes in VDJ joining. Science 229:139099393. [PubMed][CrossRef]
5. Mullighan CG, Miller CB, Radtke I, Phillips LA, Dalton J, Ma J, White D, Hughes TP, Le Beau MM, Pui CH, Relling MV, Shurtleff SA, Downing JR. 2008. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature 453:1101314. [PubMed][CrossRef]
6. Zhang J, Ding L, Holmfeldt L, Wu G, Heatley SL, Payne-Turner D, Easton J, Chen X, Wang J, Rusch M, Lu C, Chen SC, Wei L, Collins-Underwood JR, Ma J, Roberts KG, Pounds SB, Ulyanov A, Becksfort J, Gupta P, Huether R, Kriwacki RW, Parker M, McGoldrick DJ, Zhao D, Alford D, Espy S, Bobba KC, Song G, Pei D, Cheng C, Roberts S, Barbato MI, Campana D, Coustan-Smith E, Shurtleff SA, Raimondi SC, Kleppe M, Cools J, Shimano KA, Hermiston ML, Doulatov S, Eppert K, Laurenti E, Notta F, Dick JE, Basso G, Hunger SP, Loh ML, Devidas M, Wood B, Winter S, Dunsmore KP, Fulton RS, Fulton LL, Hong X, Harris CC, Dooling DJ, Ochoa K, Johnson KJ, Obenauer JC, Evans WE, Pui CH, Naeve CW, Ley TJ, Mardis ER, Wilson RK, Downing JR, Mullighan CG. 2012. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 481:1575163. [PubMed][CrossRef]
7. Papaemmanuil E, Rapado I, Li Y, Potter NE, Wedge DC, Tubio J, Alexandrov LB, Van Loo P, Cooke SL, Marshall J, Martincorena I, Hinton J, Gundem G, van Delft FW, Nik-Zainal S, Jones DR, Ramakrishna M, Titley I, Stebbings L, Leroy C, Menzies A, Gamble J, Robinson B, Mudie L, Raine K, O'Meara S, Teague JW, Butler AP, Cazzaniga G, Biondi A, Zuna J, Kempski H, Muschen M, Ford AM, Stratton MR, Greaves M, Campbell PJ. 2014. RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia. Nat Genet 46:1161:25. [PubMed][CrossRef]
8. Schatz DG, Swanson PC. 2011. V(D)J recombination: mechanisms of initiation. Annu Rev Genet 45:1676:02. [PubMed]
9. Helmink BA, Sleckman BP. 2012. The response to and repair of RAG-mediated DNA double-strand breaks. Annu Rev Immunol 30:1757:02. [PubMed]
10. Bassing CH, Alt FW, Hughes MM, D'Auteuil M, Wehrly TD, Woodman BB, Gartner F, White JM, Davidson L, Sleckman BP. 2000. Recombination signal sequences restrict chromosomal V(D)J recombination beyond the 12/23 rule. Nature 405:5838586. [PubMed]
11. Hesse JE, Lieber MR, Gellert M, Mizuuchi K. 1987. Extrachromosomal DNA substrates in pre-B cells undergo inversion or deletion at immunoglobulin V-(D)-J joining signals. Cell 49:7757:83. [CrossRef]
12. Lewis SM, Hesse JE, Mizuuchi K, Gellert M. 1988. Novel strand exchanges in V(D)J recombination. Cell 55:109909107. [PubMed][CrossRef]
13. Hesse JE, Lieber MR, Mizuuchi K, Gellert M. 1989. V(D)J recombination: a functional definition of the joining signals. Genes Dev 3:105305061. [PubMed][CrossRef]
14. Ramsden DA, McBlane JF, van Gent DC, Gellert M. 1996. Distinct DNA sequence and structure requirements for the two steps of V(D)J recombination signal cleavage. EMBO J 15:319719206. [PubMed]
15. Cuomo CA, Mundy CL, Oettinger MA. 1996. DNA sequence and structure requirements for cleavage of V(D)J recombination signal sequences. Mol Cell Biol 16:568368690. [PubMed]
16. Kale SB, Landree MA, Roth DB. 2001. Conditional RAG-1 mutants block the hairpin formation step of V(D)J recombination. Mol Cell Biol 21:4595:66. [PubMed][CrossRef]
17. Bischerour J, Lu C, Roth DB, Chalmers R. 2009. Base flipping in V(D)J recombination: insights into the mechanism of hairpin formation, the 12/23 rule, and the coordination of double-strand breaks. Mol Cell Biol 29:588988899. [PubMed][CrossRef]
18. Oettinger MA, Schatz DG, Gorka C, Baltimore D. 1990. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science 248:151751523. [PubMed][CrossRef]
19. van Gent DC, Hiom K, Paull TT, Gellert M. 1997. Stimulation of V(D)J cleavage by high mobility group proteins. EMBO J 16:266566670. [PubMed][CrossRef]
20. Thompson CB. 1995. New insights into V(D)J recombination and its role in the evolution of the immune system. Immunity 3:5313m39. [PubMed]
21. van Gent DC, Mizuuchi K, Gellert M. 1996. Similarities between initiation of V(D)J recombination and retroviral integration. Science 271:159259594. [PubMed][CrossRef]
22. Agrawal A, Eastman QM, Schatz DG. 1998. Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system. Nature 394:7444451. [PubMed]
23. Hiom K, Melek M, Gellert M. 1998. DNA transposition by the RAG1 and RAG2 proteins: a possible source of oncogenic translocations. Cell 94:4636:70. [PubMed][CrossRef]
24. Litman GW, Rast JP, Fugmann SD. 2010. The origins of vertebrate adaptive immunity. Nat Rev Immunol 10:5434:53. [PubMed][CrossRef]
25. Silver DP, Spanopoulou E, Mulligan RC, Baltimore D. 1993. Dispensable sequence motifs in the RAG-1 and RAG-2 genes for plasmid V(D)J recombination. Proc Natl Acad Sci U S A 90:610010104. [PubMed][CrossRef]
26. Sadofsky MJ, Hesse JE, McBlane JF, Gellert M. 1994. Expression and V(D)J recombination activity of mutated RAG-1 proteins. Nucleic Acids Res 22:550. [PubMed][CrossRef]
27. Dudley DD, Sekiguchi J, Zhu C, Sadofsky MJ, Whitlow S, DeVido J, Monroe RJ, Bassing CH, Alt FW. 2003. Impaired V(D)J recombination and lymphocyte development in core RAG1-expressing mice. J Exp Med 198:143943450. [PubMed][CrossRef]
28. Cuomo CA, Oettinger MA. 1994. Analysis of regions of RAG-2 important for V(D)J recombination. Nucleic Acids Res 22:181081814. [PubMed][CrossRef]
29. Sadofsky MJ, Hesse JE, Gellert M. 1994. Definition of a core region of RAG-2 that is functional in V(D)J recombination. Nucleic Acids Res 22:180580809. [PubMed][CrossRef]
30. Coussens MA, Wendland RL, Deriano L, Lindsay CR, Arnal SM, Roth DB. 2013. RAG23s acidic hinge restricts repair-pathway choice and promotes genomic stability. Cell Rep 4:8707l78. [PubMed]
31. Callebaut I, Mornon JP. 1998. The V(D)J recombination activating protein RAG2 consists of a six-bladed propeller and a PHD fingerlike domain, as revealed by sequence analysis. Cell Mol Life Sci 54:8808:91. [PubMed]
32. Akamatsu Y, Monroe R, Dudley DD, Elkin SK, Gartner F, Talukder SR, Takahama Y, Alt FW, Bassing CH, Oettinger MA. 2003. Deletion of the RAG2 C terminus leads to impaired lymphoid development in mice. Proc Natl Acad Sci U S A 100:120920214. [PubMed][CrossRef]
33. Curry JD, Schlissel MS. 2008. RAG2's non-core domain contributes to the ordered regulation of V(D)J recombination. Nucleic Acids Res 36:575075762. [PubMed][CrossRef]
34. Talukder SR, Dudley DD, Alt FW, Takahama Y, Akamatsu Y. 2004. Increased frequency of aberrant V(D)J recombination products in core RAG-expressing mice. Nucleic Acids Res 32:453953549. [PubMed][CrossRef]
35. Curry JD, Schulz D, Guidos CJ, Danska JS, Nutter L, Nussenzweig A, Schlissel MS. 2007. Chromosomal reinsertion of broken RSS ends during T cell development. J Exp Med 204:229329303. [PubMed][CrossRef]
36. Deriano L, Chaumeil J, Coussens M, Multani A, Chou Y, Alekseyenko AV, Chang S, Skok JA, Roth DB. 2011. The RAG2 C terminus suppresses genomic instability and lymphomagenesis. Nature 471:1191123. [PubMed][CrossRef]
37. Zhang L, Reynolds TL, Shan X, Desiderio S. 2011. Coupling of V(D)J recombination to the cell cycle suppresses genomic instability and lymphoid tumorigenesis. Immunity 34:1636:74. [PubMed][CrossRef]
38. Gigi V, Lewis S, Shestova O, Mijuskovic M, Deriano L, Meng W, Luning Prak ET, Roth DB. 2014. RAG2 mutants alter DSB repair pathway choice in vivo and illuminate the nature of vy choice in NHEJE. Nucleic Acids Res 42:6352eic Ac
39. Liu Y, Subrahmanyam R, Chakraborty T, Sen R, Desiderio S. 2007. A plant homeodomain in RAG-2 that binds hypermethylated lysine 4 of histone H3 is necessary for efficient antigen-receptor-gene rearrangement. Immunity 27:5616:71. [PubMed][CrossRef]
40. Matthews AG, Kuo AJ, Ramon-Maiques S, Han S, Champagne KS, Ivanov D, Gallardo M, Carney D, Cheung P, Ciccone DN, Walter KL, Utz PJ, Shi Y, Kutateladze TG, Yang W, Gozani O, Oettinger MA. 2007. RAG2 PHD finger couples histone H3 lysine 4 trimethylation with V(D)J recombination. Nature 450:110610110. [PubMed][CrossRef]
41. Li Z, Dordai DI, Lee J, Desiderio S. 1996. A conserved degradation signal regulates RAG-2 accumulation during cell division and links V(D)J recombination to the cell cycle. Immunity 5:5757m89. [PubMed]
42. van Gent DC, McBlane JF, Ramsden DA, Sadofsky MJ, Hesse JE, Gellert M. 1996. Initiation of V(D)J recombinations in a cell-free system by RAG1 and RAG2 proteins. Curr Top Microbiol Immunol 217:1170. [CrossRef]
43. Hiom K, Gellert M. 1997. A stable RAG1-RAG2-DNA complex that is active in V(D)J cleavage. Cell 88:658:2.
44. Jones JM, Gellert M. 2002. Ordered assembly of the V(D)J synaptic complex ensures accurate recombination. EMBO J 21:4162–4171. [CrossRef]
45. Lee GS, Neiditch MB, Salus SS, Roth DB. 2004. RAG proteins shepherd double-strand breaks to a specific pathway, suppressing error-prone repair, but RAG nicking initiates homologous recombination. Cell 117:1717784. [CrossRef]
46. Wang G, Dhar K, Swanson PC, Levitus M, Chang Y. 2012. Real-time monitoring of RAG-catalyzed DNA cleavage unveils dynamic changes in coding end association with the coding end complex. Nucleic Acids Res 40:608208096. [PubMed][CrossRef]
47. Qiu JX, Kale SB, Yarnell Schultz H, Roth DB. 2001. Separation-of-function mutants reveal critical roles for RAG2 in both the cleavage and joining steps of V(D)J recombination. Mol Cell 7:77:e7.
48. Yarnell Schultz H, Landree MA, Qiu JX, Kale SB, Roth DB. 2001. Joining-deficient RAG1 mutants block V(D)J recombination in vivo and hairpin opening in vitro. Mol Cell 7:65:e5.
49. Tsai CL, Drejer AH, Schatz DG. 2002. Evidence of a critical architectural function for the RAG proteins in end processing, protection, and joining in V(D)J recombination. Genes Dev 16:193493949. [PubMed][CrossRef]
50. Corneo B, Wendland RL, Deriano L, Cui X, Klein IA, Wong SY, Arnal S, Holub AJ, Weller GR, Pancake BA, Shah S, Brandt VL, Meek K, Roth DB. 2007. Rag mutations reveal robust alternative end joining. Nature 449:4838986. [PubMed][CrossRef]
51. Lewis S, Gifford A, Baltimore D. 1985. DNA elements are asymmetrically joined during the site-specific recombination of kappa immunoglobulin genes. Science 228:6777885. [PubMed][CrossRef]
52. Deriano L, Roth DB. 2013. Modernizing the nonhomologous end-joining repertoire: alternative and classical NHEJ share the stage. Annu Rev Genet 47:4333:55. [PubMed]
53. Yan CT, Boboila C, Souza EK, Franco S, Hickernell TR, Murphy M, Gumaste S, Geyer M, Zarrin AA, Manis JP, Rajewsky K, Alt FW. 2007. IgH class switching and translocations use a robust non-classical end-joining pathway. Nature 449:4787982. [PubMed][CrossRef]
54. Simsek D, Brunet E, Wong SY, Katyal S, Gao Y, McKinnon PJ, Lou J, Zhang L, Li J, Rebar EJ, Gregory PD, Holmes MC, Jasin M. 2011. DNA ligase III promotes alternative nonhomologous end-joining during chromosomal translocation formation. PLoS Genet 7:e1002080. [PubMed][CrossRef]
55. Boboila C, Alt FW, Schwer B. 2012. Classical and alternative end-joining pathways for repair of lymphocyte-specific and general DNA double-strand breaks. Adv Immunol 116:1169. [PubMed][CrossRef]
56. Haluska FG, Finver S, Tsujimoto Y, Croce CM. 1986. The t(8; 14) chromosomal translocation occurring in B-cell malignancies results from mistakes in V-D-J joining. Nature 324:1585461. [PubMed][CrossRef]
57. Kagan J, Finan J, Letofsky J, Besa EC, Nowell PC, Croce CM. 1987. α-Chain locus of the T-cell antigen receptor is involved in the t(10;14) chromosome translocation of T-cell acute lymphocytic leukemia. Proc Natl Acad Sci U S A 84:454354546. [PubMed][CrossRef]
58. Haydu JE, De Keersmaecker K, Duff MK, Paietta E, Racevskis J, Wiernik PH, Rowe JM, Ferrando A. 2012. An activating intragenic deletion in NOTCH1 in human T-ALL. Blood 119:521121214. [PubMed][CrossRef]
59. Vanura K, Montpellier B, Le T, Spicuglia S, Navarro JM, Cabaud O, Roulland S, Vachez E, Prinz I, Ferrier P, Marculescu R, Jager U, Nadel B. 2007. In vivo reinsertion of excised episomes by the V(D)J recombinase: a potential threat to genomic stability. PLoS Biol 5:e43. [PubMed][CrossRef]
60. Mijuskovic M, Brown SM, Tang Z, Lindsay CR, Efstathiadis E, Deriano L, Roth DB. 2012. A streamlined method for detecting structural variants in cancer genomes by short read paired-end sequencing. PLoS One 7:e48314. [PubMed][CrossRef]
61. Mendes RD, Sarmento LM, Cante-Barrett K, Zuurbier L, Buijs-Gladdines JG, Povoa V, Smits WK, Abecasis M, Yunes JA, Sonneveld E, Horstmann MA, Pieters R, Barata JT, Meijerink JP. 2014. PTEN micro-deletions in T-cell acute lymphoblastic leukemia are caused by illegitimate RAG-mediated recombination events. Blood 124:567:do-d [PubMed][CrossRef]
62. Lewis SM, Agard E, Suh S, Czyzyk L. 1997. Cryptic signals and the fidelity of V(D)J joining. Mol Cell Biol 17:312512136. [PubMed]
63. Zhu C, Mills KD, Ferguson DO, Lee C, Manis J, Fleming J, Gao Y, Morton CC, Alt FW. 2002. Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations. Cell 109:8111921. [PubMed][CrossRef]
64. Aplan PD, Lombardi DP, Ginsberg AM, Cossman J, Bertness VL, Kirsch IR. 1990. Disruption of the human SCL locus by “illegitimate” V-(D)-J recombinase activity. Science 250:142642429. [PubMed][CrossRef]
65. Ashworth TD, Pear WS, Chiang MY, Blacklow SC, Mastio J, Xu L, Kelliher M, Kastner P, Chan S, Aster JC. 2010. Deletion-based mechanisms of Notch1 activation in T-ALL: key roles for RAG recombinase and a conserved internal translational start site in Notch1. Blood 116:545545464. [PubMed][CrossRef]
66. Raghavan SC, Swanson PC, Wu X, Hsieh CL, Lieber MR. 2004. A non-B-DNA structure at the Bcl-2 major breakpoint region is cleaved by the RAG complex. Nature 428:88283. [PubMed][CrossRef]
67. Lewis SM. 1994. The mechanism of V(D)J joining: lessons from molecular, immunological, and comparative analyses. Adv Immunol 56:276:50.
68. Marculescu R, Le T, Simon P, Jaeger U, Nadel B. 2002. V(D)J-mediated translocations in lymphoid neoplasms: a functional assessment of genomic instability by cryptic sites. J Exp Med 195:85958. [CrossRef]
69. Chatterji M, Tsai CL, Schatz DG. 2006. Mobilization of RAG-generated signal ends by transposition and insertion in vivo. Mol Cell Biol 26:155855568. [PubMed][CrossRef]
70. Reddy YV, Perkins EJ, Ramsden DA. 2006. Genomic instability due to V(D)J recombination-associated transposition. Genes Dev 20:157557582. [PubMed][CrossRef]
71. Messier TL, O'Neill JP, Hou SM, Nicklas JA, Finette BA. 2003. In vivo transposition mediated by V(D)J recombinase in human T lymphocytes. EMBO J 22:138138388. [PubMed][CrossRef]
72. Roth DB, Craig NL. 1998. VDJ recombination: a transposase goes to work. Cell 94:4111:14. [PubMed]
73. Barreto V, Marques R, Demengeot J. 2001. Early death and severe lymphopenia caused by ubiquitous expression of the Rag1 and Rag2 genes in mice. Eur J Immunol 31:376376772. [PubMed][CrossRef]
74. Jones JM, Gellert M. 2003. Autoubiquitylation of the V(D)J recombinase protein RAG1. Proc Natl Acad Sci U S A 100:15446545451. [PubMed][CrossRef]
75. Yurchenko V, Xue Z, Sadofsky M. 2003. The RAG1 N-terminal domain is an E3 ubiquitin ligase. Genes Dev 17:5818:85. [PubMed][CrossRef]
76. Difilippantonio MJ, Zhu J, Chen HT, Meffre E, Nussenzweig MC, Max EE, Ried T, Nussenzweig A. 2000. DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation. Nature 404:5101414. [PubMed][CrossRef]
77. Gao Y, Ferguson DO, Xie W, Manis JP, Sekiguchi J, Frank KM, Chaudhuri J, Horner J, DePinho RA, Alt FW. 2000. Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development. Nature 404:8979400. [PubMed][CrossRef]
78. Bogue MA, Wang C, Zhu C, Roth DB. 1997. V(D)J recombination in Ku86-deficient mice: distinct effects on coding, signal, and hybrid joint formation. Immunity 7:37:m7. [PubMed]
79. Lieber MR. 2010. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu Rev Biochem 79:1818:11. [PubMed][CrossRef]
80. Grundy GJ, Yang W, Gellert M. 2010. Autoinhibition of DNA cleavage mediated by RAG1 and RAG2 is overcome by an epigenetic signal in V(D)J recombination. Proc Natl Acad Sci U S A 107:22487242492. [PubMed][CrossRef]
81. Elkin SK, Matthews AG, Oettinger MA. 2003. The C-terminal portion of RAG2 protects against transposition in vitro. EMBO J 22:193193938. [PubMed][CrossRef]
82. Swanson PC, Volkmer D, Wang L. 2004. 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 279:403403044.
83. Chaumeil J, Micsinai M, Ntziachristos P, Roth DB, Aifantis I, Kluger Y, Deriano L, Skok JA. 2013. The RAG2 C-terminus and ATM protect genome integrity by controlling antigen receptor gene cleavage. Nat Commun 4:2231. [PubMed]
84. Bredemeyer AL, Huang CY, Walker LM, Bassing CH, Sleckman BP. 2008. Aberrant V(D)J recombination in ataxia telangiectasia mutated-deficient lymphocytes is dependent on nonhomologous DNA end joining. J Immunol 181:262062625. [PubMed][CrossRef]
85. Mahowald GK, Baron JM, Mahowald MA, Kulkarni S, Bredemeyer AL, Bassing CH, Sleckman BP. 2009. Aberrantly resolved RAG-mediated DNA breaks in Atm-deficient lymphocytes target chromosomal breakpoints in cis. Proc Natl Acad Sci U S A 106:18339838344. [PubMed][CrossRef]
86. Celeste A, Difilippantonio S, Difilippantonio MJ, Fernandez-Capetillo O, Pilch DR, Sedelnikova OA, Eckhaus M, Ried T, Bonner WM, Nussenzweig A. 2003. H2AX haploinsufficiency modifies genomic stability and tumor susceptibility. Cell 114:3717483. [PubMed][CrossRef]
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2014-11-21
2017-11-23

Abstract:

V(D)J recombination, the mechanism responsible for generating antigen receptor diversity, has the potential to generate aberrant DNA rearrangements in developing lymphocytes. Indeed, the recombinase has been implicated in several different kinds of errors leading to oncogenic transformation. Here we review the basic aspects of V(D)J recombination, mechanisms underlying aberrant DNA rearrangements, and the types of aberrant events uncovered in recent genomewide analyses of lymphoid neoplasms.

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FIGURE 1

Antigen receptor variable exons are assembled by V(D)J recombination. Assembly of a complete variable exon occurs in two steps (in the case of an Ig heavy chain gene or a T-cell receptor β or δ gene), as shown. First, a D and a J segment are chosen from among several possibilities and are brought together to form a D-J rearrangement. A V region is then selected and joined with the D-J rearrangement to form a complete VDJ exon. Ig light chain genes and T-cell receptor α and γ genes rearrange in a single step, involving V-J recombination, as D segments are absent from these loci. C denotes the constant region exon. doi:10.1128/microbiolspec.MDNA3-0041-2014.f1

Source: microbiolspec November 2014 vol. 2 no. 6 doi:10.1128/microbiolspec.MDNA3-0041-2014
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FIGURE 2

Consensus RSS. The consensus RSS is shown, with the heptamer abutting the coding flank. The most highly conserved positions of the heptamer and nonamer are shaded in red, with conservation (%) given below. Sequence conservation data are from ( 13 ). doi:10.1128/microbiolspec.MDNA3-0041-2014.f2

Source: microbiolspec November 2014 vol. 2 no. 6 doi:10.1128/microbiolspec.MDNA3-0041-2014
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FIGURE 3

Products of V(D)J recombination. Inversional and deletional recombination are shown in the top portion of the figure. Whether recombination proceeds in a deletional or inversional manner is specified by the relative orientation of the two RSSs. Hybrid joint formation is shown at the bottom of the figure and involves an inappropriate joining of a coding end to a signal end. The reciprocal hybrid joint product, in this case an excised circle, is not shown. doi:10.1128/microbiolspec.MDNA3-0041-2014.f3

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FIGURE 4

The biochemistry of cleavage. Cleavage occurs at the junction between the heptamer and the adjoining coding flank, and occurs in two steps, as described in the text. doi:10.1128/microbiolspec.MDNA3-0041-2014.f4

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FIGURE 5

V(D)J recombination overview. Recombination is thought to be initiated by binding of the RAG proteins to a single 12-RSS (not shown), which then captures the 23-RSS to form a synaptic complex ( 44 ). RAG1/2 complexes are shown as shaded circles. Double-strand break formation generates a DNA–protein complex, the post-cleavage complex, which then helps to control the “shepherding” of the broken DNA ends to the classical nonhomologous end-joining machinery (cNHEJ; left), preventing the ends from accessing other repair mechanisms such as the alternative nonhomologous end-joining machinery (aNHEJ) or homologous recombination (HR) (right). doi:10.1128/microbiolspec.MDNA3-0041-2014.f5

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FIGURE 6

V(D)J recombination: recognition errors. Three types of recognition error are shown. (a) Recombination occurs between an authentic RSS (black triangle) with its associated coding flank (white box) and a cryptic RSS (cRSS; green triangle) with its associated coding flank (orange box), located on a separate DNA molecule. Recombination produces a rearrangement, with a pseudo-coding joint and a pseudo-signal joint. (b) The recombinase recognizes a pair of cRSSs located on separate DNA molecules. These recombine, generating a reciprocal chromosome translocation. The two products bear a pseudo-coding joint and a pseudo-signal joint. (c) The recombinase recognizes a pair of cRSSs located on the same DNA molecule and generates a deletion, forming a pseudo-coding joint (retained on the chromosome) and an excised circle containing a pseudo-signal joint. doi:10.1128/microbiolspec.MDNA3-0041-2014.f6

Source: microbiolspec November 2014 vol. 2 no. 6 doi:10.1128/microbiolspec.MDNA3-0041-2014
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FIGURE 7

V(D)J recombination: joining errors. Two versions of a three-break event (end donation) are shown. (a) An event occurring between a normal V(D)J recombination event involving authentic RSSs and a chromosome break generated by some other means (break in the red DNA molecule). (b) A similar event, this time involving a V(D)J recombination event involving a pair of cRSSs. doi:10.1128/microbiolspec.MDNA3-0041-2014.f7

Source: microbiolspec November 2014 vol. 2 no. 6 doi:10.1128/microbiolspec.MDNA3-0041-2014
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