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Activation-induced Cytidine Deaminase in B Cell Immunity and Cancers

  • Park, Seok-Rae (Department of Microbiology, College of Medicine, Konyang University)
  • Received : 2012.10.29
  • Accepted : 2012.11.13
  • Published : 2012.12.31

Abstract

Activation-induced cytidine deaminase (AID) is an enzyme that is predominantly expressed in germinal center B cells and plays a pivotal role in immunoglobulin class switch recombination and somatic hypermutation for antibody (Ab) maturation. These two genetic processes endow Abs with protective functions against a multitude of antigens (pathogens) during humoral immune responses. In B cells, AID expression is regulated at the level of either transcriptional activation on AID gene loci or post-transcriptional suppression of AID mRNA. Furthermore, AID stabilization and targeting are determined by post-translational modifications and interactions with other cellular/nuclear factors. On the other hand, aberrant expression of AID causes B cell leukemias and lymphomas, including Burkitt's lymphoma caused by c-myc/IgH translocation. AID is also ectopically expressed in T cells and non-immune cells, and triggers point mutations in relevant DNA loci, resulting in tumorigenesis. Here, I review the recent literatures on the function of AID, regulation of AID expression, stability and targeting in B cells, and AID-related tumor formation.

Keywords

References

  1. Chaudhuri, J. and F. W. Alt. 2004. Class-switch recombination: interplay of transcription, DNA deamination and DNA repair. Nat. Rev. Immunol. 4: 541-552. https://doi.org/10.1038/nri1395
  2. Di Noia, J. M. and M. S. Neuberger. 2007. Molecular mechanisms of antibody somatic hypermutation. Annu. Rev. Biochem. 76: 1-22. https://doi.org/10.1146/annurev.biochem.76.061705.090740
  3. Peled, J. U., F. L. Kuang, M. D. Iglesias-Ussel, S. Roa, S. L. Kalis, M. F. Goodman, and M. D. Scharff. 2008. The biochemistry of somatic hypermutation. Annu. Rev. Immunol. 26: 481-511. https://doi.org/10.1146/annurev.immunol.26.021607.090236
  4. Stavnezer, J., J. E. Guikema, and C. E. Schrader. 2008. Mechanism and regulation of class switch recombination. Annu. Rev. Immunol. 26: 261-292. https://doi.org/10.1146/annurev.immunol.26.021607.090248
  5. Arakawa, H., J. Hauschild, and J. M. Buerstedde. 2002. Requirement of the activation-induced deaminase (AID) gene for immunoglobulin gene conversion. Science 295: 1301-1306. https://doi.org/10.1126/science.1067308
  6. Harris, R. S., J. E. Sale, S. K. Petersen-Mahrt, and M. S. Neuberger. 2002. AID is essential for immunoglobulin V gene conversion in a cultured B cell line. Curr. Biol. 12:435-438. https://doi.org/10.1016/S0960-9822(02)00717-0
  7. Muramatsu, M., K. Kinoshita, S. Fagarasan, S. Yamada, Y. Shinkai, and T. Honjo. 2000. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102: 553-563. https://doi.org/10.1016/S0092-8674(00)00078-7
  8. Revy, P., T. Muto, Y. Levy, F. Geissmann, A. Plebani, O. Sanal, N. Catalan, M. Forveille, R. Dufourcq-Labelouse, A. Gennery, I. Tezcan, F. Ersoy, H. Kayserili, A. G. Ugazio, N. Brousse, M. Muramatsu, L. D. Notarangelo, K. Kinoshita, T. Honjo, A. Fischer, and A. Durandy. 2000. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell 102: 565-575. https://doi.org/10.1016/S0092-8674(00)00079-9
  9. Mechtcheriakova, D., M. Svoboda, A. Meshcheryakova, and E. Jensen-Jarolim. 2012. Activation-induced cytidine deaminase (AID) linking immunity, chronic inflammation, and cancer. Cancer Immunol. Immunother. 61: 1591-1598. https://doi.org/10.1007/s00262-012-1255-z
  10. Muramatsu, M., V. S. Sankaranand, S. Anant, M. Sugai, K. Kinoshita, N. O. Davidson, and T. Honjo. 1999. Specific expression of activation-induced cytidine deaminase (AID), a novel member of the RNA-editing deaminase family in germinal center B cells. J. Biol. Chem. 274: 18470-18476. https://doi.org/10.1074/jbc.274.26.18470
  11. Okazaki, I. M., K. Kinoshita, M. Muramatsu, K. Yoshikawa, and T. Honjo. 2002. The AID enzyme induces class switch recombination in fibroblasts. Nature 416: 340-345. https://doi.org/10.1038/nature727
  12. Yoshikawa, K., I. M. Okazaki, T. Eto, K. Kinoshita, M. Muramatsu, H. Nagaoka, and T. Honjo. 2002. AID enzyme- induced hypermutation in an actively transcribed gene in fibroblasts. Science 296: 2033-2036. https://doi.org/10.1126/science.1071556
  13. Stavnezer, J. 2000. Molecular processes that regulate class switching. Curr. Top. Microbiol. Immunol. 245: 127-168.
  14. Jung, S., K. Rajewsky, and A. Radbruch. 1993. Shutdown of class switch recombination by deletion of a switch region control element. Science 259: 984-987. https://doi.org/10.1126/science.8438159
  15. Petersen-Mahrt, S. K., R. S. Harris, and M. S. Neuberger. 2002. AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification. Nature 418: 99-103.
  16. Bransteitter, R., P. Pham, M. D. Scharff, and M. F. Goodman. 2003. Activation-induced cytidine deaminase deaminates deoxycytidine on single-stranded DNA but requires the action of RNase. Proc. Natl. Acad. Sci. U.S.A. 100:4102-4107. https://doi.org/10.1073/pnas.0730835100
  17. Chaudhuri, J., M. Tian, C. Khuong, K. Chua, E. Pinaud, and F. W. Alt. 2003. Transcription-targeted DNA deamination by the AID antibody diversification enzyme. Nature 422: 726-730. https://doi.org/10.1038/nature01574
  18. Dickerson, S. K., E. Market, E. Besmer, and F. N. Papavasiliou. 2003. AID mediates hypermutation by deaminating single stranded DNA. J. Exp. Med. 197: 1291-1296. https://doi.org/10.1084/jem.20030481
  19. Pham, P., R. Bransteitter, J. Petruska, and M. F. Goodman. 2003. Processive AID-catalysed cytosine deamination on single- stranded DNA simulates somatic hypermutation. Nature 424: 103-107. https://doi.org/10.1038/nature01760
  20. Ramiro, A. R., P. Stavropoulos, M. Jankovic, and M. C. Nussenzweig. 2003. Transcription enhances AID-mediated cytidine deamination by exposing single-stranded DNA on the nontemplate strand. Nat. Immunol. 4: 452-456. https://doi.org/10.1038/ni920
  21. Sohail, A., J. Klapacz, M. Samaranayake, A. Ullah, and A. S. Bhagwat. 2003. Human activation-induced cytidine deaminase causes transcription-dependent, strand-biased C to U deaminations. Nucleic Acids Res. 31: 2990-2994. https://doi.org/10.1093/nar/gkg464
  22. Neuberger, M. S., J. M. Di Noia, R. C. Beale, G. T. Williams, Z. Yang, and C. Rada. 2005. Somatic hypermutation at A.T pairs: polymerase error versus dUTP incorporation. Nat. Rev. Immunol. 5: 171-178. https://doi.org/10.1038/nri1553
  23. Guikema, J. E., E. K. Linehan, D. Tsuchimoto, Y. Nakabeppu, P. R. Strauss, J. Stavnezer, and C. E. Schrader. 2007. APE1- and APE2-dependent DNA breaks in immunoglobulin class switch recombination. J. Exp. Med. 204: 3017-3026. https://doi.org/10.1084/jem.20071289
  24. Stavnezer, J. 2011. Complex regulation and function of activation- induced cytidine deaminase. Trends Immunol. 32: 194-201. https://doi.org/10.1016/j.it.2011.03.003
  25. Pavri, R. and M. C. Nussenzweig. 2011. AID targeting in antibody diversity. Adv. Immunol. 110: 1-26.
  26. Arakawa, H. and J. M. Buerstedde. 2009. Activation-induced cytidine deaminase-mediated hypermutation in the DT40cell line. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 364: 639-644. https://doi.org/10.1098/rstb.2008.0202
  27. Kuraoka, M., T. M. Holl, D. Liao, M. Womble, D. W. Cain, A. E. Reynolds, and G. Kelsoe. 2011. Activation-induced cytidine deaminase mediates central tolerance in B cells. Proc. Natl. Acad. Sci. U.S.A. 108: 11560-11565. https://doi.org/10.1073/pnas.1102571108
  28. Meyers, G., Y. S. Ng, J. M. Bannock, A. Lavoie, J. E. Walter, L. D. Notarangelo, S. S. Kilic, G. Aksu, M. Debré, F. Rieux-Laucat, M. E. Conley, C. Cunningham-Rundles, A. Durandy, and E. Meffre. 2011. Activation-induced cytidine deaminase (AID) is required for B-cell tolerance in humans. Proc. Natl. Acad. Sci. U.S.A. 108: 11554-11559. https://doi.org/10.1073/pnas.1102600108
  29. Kuraoka, M. and G. Kelsoe. 2011. A novel role for activation- induced cytidine deaminase: central B-cell tolerance. Cell Cycle 10: 3423-3424. https://doi.org/10.4161/cc.10.20.17693
  30. Péron, S., B. Laffleur, N. Denis-Lagache, J. Cook-Moreau, A. Tinguely, L. Delpy, Y. Denizot, E. Pinaud, and M. Cogne. 2012. AID-driven deletion causes immunoglobulin heavy chain locus suicide recombination in B cells. Science 336: 931-934. https://doi.org/10.1126/science.1218692
  31. Nagaoka, H., T. H. Tran, M. Kobayashi, M. Aida, and T. Honjo. 2010. Preventing AID, a physiological mutator, from deleterious activation: regulation of the genomic instability that is associated with antibody diversity. Int. Immunol. 22: 227-235. https://doi.org/10.1093/intimm/dxq023
  32. Pone, E. J., J. Zhang, T. Mai, C. A. White, G. Li, J. K. Sakakura, P. J. Patel, A. Al-Qahtani, H. Zan, Z. Xu, and P. Casali. 2012. BCR-signalling synergizes with TLR-signalling for induction of AID and immunoglobulin class-switching through the non-canonical NF-$\kappa B$ pathway. Nat. Commun. 3: 767. https://doi.org/10.1038/ncomms1769
  33. Xu, Z., H. Zan, E. J. Pone, T. Mai, and P. Casali. 2012. Immunoglobulin class-switch DNA recombination: induction, targeting and beyond. Nat. Rev. Immunol. 12: 517-531. https://doi.org/10.1038/nri3216
  34. Zan, H. and P. Casali. 2012. Regulation of Aicda expression and AID activity. Autoimmunity doi:10.3109/08916934.2012. 749244.
  35. Kim, R. J., H. A. Kim, J. B. Park, S. R. Park, S. H. Jeon, G. Y. Seo, D. W. Seo, S. R. Seo, G. T. Chun, N. S. Kim, S. W. Yie, W. H. Byeon, and P. H. Kim. 2007. IL-4-induced AID expression and its relevance to IgA class switch recombination. Biochem. Biophys. Res. Commun. 361: 398-403. https://doi.org/10.1016/j.bbrc.2007.07.022
  36. Kim, H. A., G. Y. Seo, and P. H. Kim. 2011. Macrophage- derived BAFF induces AID expression through the p38MAPK/CREB and JNK/AP-1 pathways. J. Leukoc. Biol. 89: 393-398. https://doi.org/10.1189/jlb.1209787
  37. Park, S. R., H. Zan, Z. Pal, J. Zhang, A. Al-Qahtani, E. J. Pone, Z. Xu, T. Mai, and P. Casali. 2009. HoxC4 binds to the promoter of the cytidine deaminase AID gene to induce AID expression, class-switch DNA recombination and somatic hypermutation. Nat. Immunol. 10: 540-550. https://doi.org/10.1038/ni.1725
  38. Park, S. R., P. H. Kim, K. S. Lee, S. H. Lee, G. Y. Seo, Y. C. Yoo, J. Lee, and P. Casali. 2012. APRIL stimulates NF-$\kappa B$-mediated HoxC4 induction for AID expression in mouse B cells. Cytokine doi:10.1016/j.cyto.2012.10.018.
  39. Seidl, T., T. Whittall, K. Babaahmady, and T. Lehner. 2012. B-cell agonists up-regulate AID and APOBEC3G deaminases, which induce IgA and IgG class antibodies and anti-viral function. Immunology 135: 207-215. https://doi.org/10.1111/j.1365-2567.2011.03524.x
  40. Lee, M. R., G. Y. Seo, Y. M. Kim, and P. H. Kim. 2011. iNOS potentiates mouse Ig isotype switching through AID expression. Biochem. Biophys. Res. Commun. 410: 602-607. https://doi.org/10.1016/j.bbrc.2011.06.035
  41. Hauser, J., N. Sveshnikova, A. Wallenius, S. Baradaran, J. Saarikettu, and T. Grundström. 2008. B-cell receptor activation inhibits AID expression through calmodulin inhibition of E-proteins. Proc. Natl. Acad. Sci. U.S.A. 105: 1267-1272. https://doi.org/10.1073/pnas.0708220105
  42. Pauklin, S. and S. K. Petersen-Mahrt. 2009. Progesterone inhibits activation-induced deaminase by bindingto the promoter. J. Immunol. 183: 1238-1244. https://doi.org/10.4049/jimmunol.0803915
  43. Sayegh, C. E., M. W. Quong, Y. Agata, and C. Murre. 2003. E-proteins directly regulate expression of activation-induced deaminase in mature B cells. Nat. Immunol. 4: 586-593. https://doi.org/10.1038/ni923
  44. Gonda, H., M. Sugai, Y. Nambu, T. Katakai, Y. Agata, K. J. Mori, Y. Yokota, and A. Shimizu. 2003. The balance between Pax5 and Id2 activities is the key to AID gene expression. J. Exp. Med. 198: 1427-1437. https://doi.org/10.1084/jem.20030802
  45. Lee, C. H., M. Melchers, H. Wang, T. A. Torrey, R. Slota, C. F. Qi, J. Y. Kim, P. Lugar, H. J. Kong, L. Farrington, B. van der Zouwen, J. X. Zhou, V. Lougaris, P. E. Lipsky, A. C. Grammer, and H. C. 3rd Morse. 2006. Regulation of the germinal center gene program by interferon (IFN) regulatory factor 8/IFN consensus sequence-binding protein. J. Exp. Med. 203: 63-72. https://doi.org/10.1084/jem.20051450
  46. Yadav, A., A. Olaru, M. Saltis, A. Setren, J. Cerny, and F. Livák. 2006. Identification of a ubiquitously active promoter of the murine activation-induced cytidine deaminase (AICDA) gene. Mol. Immunol. 43: 529-541. https://doi.org/10.1016/j.molimm.2005.05.007
  47. Tran, T. H., M. Nakata, K. Suzuki, N. A. Begum, R. Shinkura, S. Fagarasan, T. Honjo, and H. Nagaoka. 2010. B cell-specificand stimulation-responsive enhancers derepress Aicda by overcoming the effects of silencers. Nat. Immunol. 11: 148-154. https://doi.org/10.1038/ni.1829
  48. Pauklin, S., I. V. Sernández, G. Bachmann, A. R. Ramiro, and S. K. Petersen-Mahrt. 2009. Estrogen directly activates AID transcription and function. J. Exp. Med. 206: 99-111. https://doi.org/10.1084/jem.20080521
  49. Mai, T., H. Zan, J. Zhang, J. S. Hawkins, Z. Xu, and P. Casali. 2010. Estrogen receptors bind to and activate the HOXC4/HoxC4 promoter to potentiate HoxC4-mediated activation- induced cytosine deaminase induction, immunoglobulin class switch DNA recombination, and somatic hypermutation. J. Biol. Chem. 285: 37797-37810. https://doi.org/10.1074/jbc.M110.169086
  50. Lee, H., J. S. Trott, S. Haque, S. McCormick, N. Chiorazzi,and P. K. Mongini. 2010. A cyclooxygenase-2/prostaglandin E2 pathway augments activation-induced cytosine deaminase expression within replicating human B cells. J. Immunol. 185: 5300-5314. https://doi.org/10.4049/jimmunol.1000574
  51. Ise, W., M. Kohyama, B. U. Schraml, T. Zhang, B. Schwer, U. Basu, F. W. Alt, J. Tang, E. M. Oltz, T. L. Murphy, and K. M. Murphy. 2011. Nat. Immunol. 12: 536-543. https://doi.org/10.1038/ni.2037
  52. Luo, H. and M. Tian. 2010. Transcription factors PU.1 and IRF4 regulate activation induced cytidine deaminase in chicken B cells. Mol. Immunol. 47: 1383-1395. https://doi.org/10.1016/j.molimm.2010.02.016
  53. Pritchard, C. C., H. H. Cheng, and M. Tewari. 2012. Micro- RNA profiling: approaches and considerations. Nat. Rev. Genet. 13: 358-369.
  54. Teng, G., P. Hakimpour, P. Landgraf, A. Rice, T. Tuschl, R. Casellas, and F. N. Papavasiliou. 2008. MicroRNA-155 is a negative regulator of activation-induced cytidine deaminase. Immunity 28: 621-629. https://doi.org/10.1016/j.immuni.2008.03.015
  55. Dorsett, Y., K. M. McBride, M. Jankovic, A. Gazumyan, T. H. Thai, D. F. Robbiani, M. Di Virgilio, B. Reina San-Martin, G. Heidkamp, T. A. Schwickert, T. Eisenreich, K. Rajewsky, and M. C. Nussenzweig. 2008. MicroRNA-155 suppresses activation- induced cytidine deaminase-mediated Myc-Igh translocation. Immunity 28: 630-638. https://doi.org/10.1016/j.immuni.2008.04.002
  56. de Yebenes, V. G., L. Belver, D. G. Pisano, S. Gonzalez, A. Villasante, C. Croce, L. He, and A. R. Ramiro. 2008. miR-181b negatively regulates activation-induced cytidine deaminase in B cells. J. Exp. Med. 205: 2199-2206. https://doi.org/10.1084/jem.20080579
  57. Borchert, G. M., N. W. Holton, and E. D. Larson. 2011. Repression of human activation induced cytidine deaminase by miR-93 and miR-155. BMC Cancer 11: 347. https://doi.org/10.1186/1471-2407-11-347
  58. Chaudhuri, J., C. Khuong, and F. W. Alt. 2004. Replication protein A interacts with AID to promote deamination of somatic hypermutation targets. Nature 430: 992-998. https://doi.org/10.1038/nature02821
  59. Basu, U., J. Chaudhuri, C. Alpert, S. Dutt, S. Ranganath, G. Li, J. P. Schrum, J. P. Manis, and F. W. Alt. 2005. The AID antibody diversification enzyme is regulatedby protein kinase A phosphorylation. Nature 438: 508-511. https://doi.org/10.1038/nature04255
  60. McBride, K. M., A. Gazumyan, E. M. Woo, V. M. Barreto, D. F. Robbiani, B. T. Chait, and M. C. Nussenzweig. 2006. Regulation of hypermutation by activation-induced cytidine deaminase phosphorylation. Proc. Natl. Acad. Sci. U.S.A. 103: 8798-8803. https://doi.org/10.1073/pnas.0603272103
  61. McBride, K. M., A. Gazumyan, E. M. Woo, T. A. Schwickert, B. T. Chait, and M. C. Nussenzweig. 2008. Regulation of class switch recombination and somatic mutation by AID phosphorylation. J. Exp. Med. 205: 2585-2594. https://doi.org/10.1084/jem.20081319
  62. Basu, U., Y. Wang, and F. W. Alt. 2008. Evolution of phosphorylation- dependent regulation of activation-induced cytidine deaminase. Mol. Cell 32: 285-291. https://doi.org/10.1016/j.molcel.2008.08.019
  63. Cheng, H. L., B. Q. Vuong, U. Basu, A. Franklin, B. Schwer, J. Astarita, R. T. Phan, A. Datta, J. Manis, F. W. Alt, and J. Chaudhuri. 2009. Integrity of the AID serine-38 phosphorylation site is critical for class switch recombination and somatic hypermutation in mice. Proc. Natl. Acad. Sci. U.S.A. 106: 2717-2722. https://doi.org/10.1073/pnas.0812304106
  64. Gazumyan, A., K. Timachova, G. Yuen, E. Siden, M. Di Virgilio, E. M. Woo, B. T. Chait, B. Reina San-Martin, M. C. Nussenzweig, and K. M. McBride. 2011. Amino-terminal phosphorylation of activation-induced cytidine deaminase suppresses c-myc/IgH translocation. Mol. Cell. Biol. 31:442-449. https://doi.org/10.1128/MCB.00349-10
  65. Demorest, Z. L., M. Li, and R. S. Harris. 2011. Phosphorylation directly regulates theintrinsic DNA cytidine deaminase activity of activation-induced deaminase and APOBEC3G protein. J. Biol. Chem. 286: 26568-26575. https://doi.org/10.1074/jbc.M111.235721
  66. Li, G., E. J. Pone, D. C. Tran, P. J. Patel, L. Dao, Z. Xu, and P. Casali. 2012. Iron inhibits activation-induced cytidine deaminase enzymatic activity and modulates immunoglobulin class switch DNA recombination. J. Biol. Chem. 287:21520-21529. https://doi.org/10.1074/jbc.M112.366732
  67. Orthwein, A., A. M. Patenaude, B. Affar el, A. Lamarre, J. C. Young, and J. M. Di Noia. 2010. Regulation of activation- induced deaminase stability and antibody gene diversification by Hsp90. J. Exp. Med. 207: 2751-2765. https://doi.org/10.1084/jem.20101321
  68. Orthwein, A., A. Zahn, S. P. Methot, D. Godin, S. G. Conticello, K. Terada, and J. M. Di Noia. 2011. Optimal functional levels of activation-induced deaminasespecifically require the Hsp40 DnaJa1. EMBO J. 31: 679-691.
  69. Häsler, J., C. Rada, and M. S. Neuberger. 2011. Cytoplasmic activation-induced cytidine deaminase (AID) exists in stoichiometric complex with translation elongation factor $1\alpha$ (eEF1A). Proc. Natl. Acad. Sci. U.S.A. 108: 18366-18371. https://doi.org/10.1073/pnas.1106729108
  70. Geisberger, R., C. Rada, and M. S. Neuberger. 2009. The stability of AID and its function in class-switching are critically sensitive to the identity of its nuclear-export sequence. Proc. Natl. Acad. Sci. U.S.A. 106: 6736-6741. https://doi.org/10.1073/pnas.0810808106
  71. Ellyard, J. I., A. S. Benk, B. Taylor, C. Rada, and M. S. Neuberger. 2011. The dependence of Ig class-switching on the nuclear export sequence of AID likely reflects interaction with factors additional to Crm1 exportin. Eur. J. Immunol. 41: 485-490. https://doi.org/10.1002/eji.201041011
  72. Arioka, Y., A. Watanabe, K. Saito, and Y. Yamada. 2012. Activation-induced cytidine deaminase alters the subcellular localization of Tet family proteins. PLoS One 7: e45031.
  73. Conticello, S. G., K. Ganesh, K. Xue, M. Lu, C. Rada, M. S. Neuberger. 2008. Interaction between antibody-diversification enzyme AID and spliceosome-associated factor CTNNBL1. Mol. Cell 31: 474-484. https://doi.org/10.1016/j.molcel.2008.07.009
  74. Hu, Y., I. Ericsson, K. Torseth, S. P. Methot, O. Sundheim, N. B. Liabakk, G. Slupphaug, J. M. Di Noia, H. E. Krokan, and B. Kavli. 2012. A Combined Nuclear and Nucleolar Localization Motif in Activation-Induced Cytidine Deaminase (AID) Controls Immunoglobulin Class Switching. J. Mol. Biol. doi:10.1016/j.jmb.2012.11.026.
  75. Zaprazna, K. and M. L. Atchison. 2012. YY1 controls immunoglobulin class switch recombination and nuclear activation- induced deaminase levels. Mol. Cell. Biol. 32: 1542-1554. https://doi.org/10.1128/MCB.05989-11
  76. Uchimura, Y., L. F. Barton, C. Rada, and M. S. Neuberger. 2011. REG-$\gamma$ associates with and modulates the abundance of nuclear activation-induced deaminase. J. Exp. Med. 208: 2385-2391. https://doi.org/10.1084/jem.20110856
  77. Vuong, B. Q., M. Lee, S. Kabir, C. Irimia, S. Macchiarulo, G. S. McKnight, and J. Chaudhuri. 2009. Specific recruitment of protein kinase A tothe immunoglobulin locus regulates class-switch recombination. Nat. Immunol. 10: 420-426.78. Xu, Z., Z. Fulop, G. Wu, E. J. Pone, J. Zhang, T. Mai, L. M. Thomas, A. Al-Qahtani, C. A. White, S. R. Park, P. Steinacker, Z. Li, J. 3rd. Yates, B. Herron, M. Otto, H. Zan, H. Fu, and P. Casali. 2010. 14-3-3 adaptor proteins recruit AID to 5'-AGCT-3'-rich switch regions for class switch recombination. Nat. Struct. Mol. Biol. 17: 1124-1135. https://doi.org/10.1038/nsmb.1884
  78. Xu, Z., Z. Fulop, G. Wu, E. J. Pone, J. Zhang, T. Mai, L. M. Thomas, A. Al-Qahtani, C. A. White, S. R. Park, P. Steinacker, Z. Li, J. 3rd. Yates, B. Herron, M. Otto, H. Zan, H. Fu, and P. Casali. 2010. 14-3-3 adaptor proteins recruit AID to 5'-AGCT-3'-rich switch regions for class switch recombination. Nat. Struct. Mol. Biol. 17: 1124-1135. https://doi.org/10.1038/nsmb.1884
  79. Nowak, U., A. J. Matthews, S. Zheng, and J. Chaudhuri. 2011. The splicing regulator PTBP2 interacts with the cytidine deaminase AID and promotes binding of AID to switch-region DNA. Nat. Immunol. 12: 160-166. https://doi.org/10.1038/ni.1977
  80. Basu, U., F. L. Meng, C. Keim, V. Grinstein, E. Pefanis, J. Eccleston, T. Zhang, D. Myers, C. R. Wasserman, D. R. Wesemann, K. Januszyk, R. I. Gregory, H. Deng, C. D. Lima, and F. W. Alt. 2011. The RNA exosome targets the AID cytidine deaminase to both strands of transcribed duplex DNA substrates. Cell 144: 353-363. https://doi.org/10.1016/j.cell.2011.01.001
  81. Jeevan-Raj, B. P., I. Robert, V. Heyer, A. Page, J. H. Wang, F. Cammas, F. W. Alt, R. Losson, and B. Reina-San-Martin. 2011. Epigenetic tethering of AID to the donor switch region during immunoglobulin class switch recombination. J. Exp. Med. 208: 1649-1660. https://doi.org/10.1084/jem.20110118
  82. Ranjit, S., L. Khair, E. K. Linehan, A. J. Ucher, M. Chakrabarti, C. E. Schrader, and J. Stavnezer. 2011. AID binds cooperatively with UNG and Msh2-Msh6 to Ig switch regions dependent upon the AID C terminus. J. Immunol. 187: 2464-2475. https://doi.org/10.4049/jimmunol.1101406
  83. Zan, H., C. A. White, L. M. Thomas, T. Mai, G. Li, Z. Xu, J. Zhang, and P. Casali. 2012. Rev1 recruits ung to switch regions and enhances du glycosylation for immunoglobulin class switch DNA recombination. Cell Rep. 2: 1220-1232. https://doi.org/10.1016/j.celrep.2012.09.029
  84. Stanlie, A., N. A. Begum, H. Akiyama, and T. Honjo. 2012. The DSIF subunits Spt4 and Spt5 have distinct roles at various phases of immunoglobulin class switch recombination. PLoS Genet. 8: e1002675. https://doi.org/10.1371/journal.pgen.1002675
  85. Pavri, R., A. Gazumyan, M. Jankovic, M. Di Virgilio, I. Klein, C. Ansarah-Sobrinho, W. Resch, A. Yamane, B. Reina San-Martin, V. Barreto, T. J. Nieland, D. E. Root, R. Casellas, and M. C. Nussenzweig. 2010. Activation-induced cytidine deaminase targets DNA at sites of RNA polymerase II stalling by interaction with Spt5. Cell 143: 122-133. https://doi.org/10.1016/j.cell.2010.09.017
  86. Okazaki, I. M., K. Okawa, M. Kobayashi, K. Yoshikawa, S. Kawamoto, H. Nagaoka, R. Shinkura, Y. Kitawaki, H. Taniguchi, T. Natsume, S. Iemura, and T. Honjo. 2011. Histone chaperone Spt6 is required for class switch recombination but not somatic hypermutation. Proc. Natl. Acad. Sci. U.S.A. 108: 7920-7925. https://doi.org/10.1073/pnas.1104423108
  87. Begum, N. A., A. Stanlie, M. Nakata, H. Akiyama, and T. Honjo. 2012. The histone chaperone Spt6 is requiredfor activation- induced cytidine deaminase target determination through H3K4me3 regulation. J. Biol. Chem. 287: 32415-32429. https://doi.org/10.1074/jbc.M112.351569
  88. Maeda, K., S. K. Singh, K. Eda, M. Kitabatake, P. Pham, M. F. Goodman, and N. Sakaguchi. 2010. GANP-mediated recruitment of activation-induced cytidine deaminase to cell nuclei and to immunoglobulin variable region DNA. J. Biol.Chem. 285: 23945-23953. https://doi.org/10.1074/jbc.M110.131441
  89. Tanaka, A., H. M. Shen, S. Ratnam, P. Kodgire, and U. Storb. 2010. Attracting AIDto targets of somatic hypermutation. J. Exp. Med. 207: 405-415. https://doi.org/10.1084/jem.20090821
  90. Kim, Y. and M. Tian. 2009. NF-kappaB family of transcription factor facilitates gene conversion in chicken B cells. Mol. Immunol. 46: 3283-3291. https://doi.org/10.1016/j.molimm.2009.07.027
  91. Kim, Y. and M. Tian. 2010. The recruitment of activation induced cytidine deaminase to the immunoglobulin locus by a regulatory element. Mol. Immunol. 47: 1860-1865. https://doi.org/10.1016/j.molimm.2010.02.025
  92. Kanehiro, Y., K. Todo, M. Negishi, J. Fukuoka, W. Gan, T. Hikasa, Y. Kaga, M. Takemoto, M. Magari, X. Li, J. L. Manley, H. Ohmori, and N. Kanayama. 2012. Activation-induced cytidine deaminase (AID)-dependent somatichypermutation requires a splice isoform of the serine/arginine-rich (SR) protein SRSF1. Proc. Natl. Acad. Sci. U.S.A. 109: 1216-1221. https://doi.org/10.1073/pnas.1120368109
  93. Robbiani, D. F. and M. C. Nussenzweig. 2012. Chromosome Translocation, B Cell Lymphoma, and Activation-induced Cytidine Deaminase. Annu. Rev. Pathol. [Epub ahead of print]
  94. Staszewski, O., R. E. Baker, A. J. Ucher, R. Martier, J. Stavnezer, and J. E. Guikema. 2011. Activation-induced cytidine deaminase induces reproducible DNA breaks at many non-Ig Loci in activated B cells. Mol. Cell 41: 232-242. https://doi.org/10.1016/j.molcel.2011.01.007
  95. Greisman, H. A., Z. Lu, A. G. Tsai, T. C. Greiner, H. S. Yi, and M. R. Lieber. 2012. IgH partner breakpoint sequences provide evidence that AID initiates t(11;14) and t(8;14) chromosomal breaks in mantle cell and Burkitt lymphomas. Blood 120: 2864-2867. https://doi.org/10.1182/blood-2012-02-412791
  96. Robbiani, D. F., S. Bunting, N. Feldhahn, A. Bothmer, J. Camps, S. Deroubaix, K. M. McBride, I. A. Klein, G. Stone, T. R. Eisenreich, T. Ried, A. Nussenzweig, and M. C. Nussenzweig. 2009. AID produces DNA double-strand breaks in non-Ig genes and mature B cell lymphomas with reciprocal chromosome translocations. Mol. Cell 36: 631-641. https://doi.org/10.1016/j.molcel.2009.11.007
  97. Jankovic, M., D. F. Robbiani, Y. Dorsett, T. Eisenreich, Y. Xu, A. Tarakhovsky, A. Nussenzweig, and M. C. Nussenzweig. 2010. Role of the translocation partner in protection against AID-dependent chromosomal translocations. Proc. Natl. Acad. Sci. U.S.A. 107: 187-192. https://doi.org/10.1073/pnas.0908946107
  98. Komeno, Y., J. Kitaura, N. Watanabe-Okochi, N. Kato, T. Oki, F. Nakahara, Y. Harada, H. Harada, R. Shinkura, H. Nagaoka, Y. Hayashi, T. Honjo, and T. Kitamura. 2010. AID-induced T-lymphoma or Bleukemia/lymphoma in a mouse BMT model. Leukemia 24: 1018-1024. https://doi.org/10.1038/leu.2010.40
  99. Feldhahn, N., N. Henke, K. Melchior, C. Duy, B. N. Soh, F. Klein, G. von Levetzow, B. Giebel, A. Li, W. K. Hofmann, H. Jumaa, and M. Müschen. 2007. Activation-induced cytidine deaminase acts as a mutator in BCR-ABL1- transformed acute lymphoblastic leukemia cells. J. Exp. Med. 204: 1157-1166. https://doi.org/10.1084/jem.20062662
  100. Klemm, L., C. Duy, I. Iacobucci, S. Kuchen, G. von Levetzow, N. Feldhahn, N. Henke, Z. Li, T. K. Hoffmann, Y. M. Kim, W. K. Hofmann, H. Jumaa, J. Groffen, N. Heisterkamp, G. Martinelli, M. R. Lieber, R. Casellas, and M. Muschen. 2009. The B cell mutator AID promotes B lymphoid blast crisis and drug resistance in chronic myeloid leukemia. Cancer Cell 16: 232-245. https://doi.org/10.1016/j.ccr.2009.07.030
  101. Iacobucci, I., A. Lonetti, F. Messa, A. Ferrari, D. Cilloni, S. Soverini, F. Paoloni, F. Arruga, E. Ottaviani, S. Chiaretti, M.Messina, M. Vignetti, C. Papayannidis, A. Vitale, F. Pane, P. P. Piccaluga, S. Paolini, G. Berton, A. Baruzzi, G. Saglio, M. Baccarani, R. Foa, and G. Martinelli. 2010. Different isoforms of the B-cell mutator activation-induced cytidine deaminase are aberrantly expressed in BCR-ABL1-positive acute lymphoblastic leukemia patients. Leukemia 24: 66-73. https://doi.org/10.1038/leu.2009.197
  102. Gruber, T. A., M. S. Chang, R. Sposto, and M. Müschen. 2010. Activation-induced cytidine deaminase accelerates clonal evolution in BCR-ABL1-driven B-cell lineage acute lymphoblastic leukemia. Cancer Res. 70: 7411-7420. https://doi.org/10.1158/0008-5472.CAN-10-1438
  103. Palacios, F., P. Moreno, P. Morande, C. Abreu, A. Correa, V. Porro, A. I. Landoni, R. Gabus, M. Giordano, G. Dighiero, O. Pritsch, and P. Oppezzo. 2010. High expression of AID and active class switch recombination might account for a more aggressive disease in unmutated CLL patients: link with an activated microenvironment in CLL disease. Blood 115: 4488-4496. https://doi.org/10.1182/blood-2009-12-257758
  104. Hancer, V. S., M. Kose, R. Diz-Kucukkaya, A. S. Yavuz, and M. Aktan. 2011. Activation-induced cytidine deaminase mRNA levels in chronic lymphocytic leukemia. Leuk. Lymphoma 52: 79-84.
  105. Qin, H., K. Suzuki, M. Nakata, S. Chikuma, N. Izumi, T. Huong le, M. Maruya, S. Fagarasan, M. Busslinger, T. Honjo, and H. Nagaoka. 2011. Activation-induced cytidine deaminase expression in CD4+ T cells is associated with a unique IL-10-producing subset that increases with age. PLoS One 6: e29141. https://doi.org/10.1371/journal.pone.0029141
  106. Ishikawa, C., S. Nakachi, M. Senba, M. Sugai, and N. Mori. 2011. Activation of AID by human T-cell leukemia virus Tax oncoprotein and the possible role of its constitutive expression in ATL genesis. Carcinogenesis 32: 110-119. https://doi.org/10.1093/carcin/bgq222
  107. Komori, J., H. Marusawa, T. Machimoto, Y. Endo, K. Kinoshita, T. Kou, H. Haga, I. Ikai, S. Uemoto, and T. Chiba. 2008. Activation-induced cytidine deaminase links bile duct inflammation to human cholangiocarcinoma. Hepatology 47: 888-896. https://doi.org/10.1002/hep.22125
  108. Endo, Y., H. Marusawa, T. Kou, H. Nakase, S. Fujii, T. Fujimori, K. Kinoshita, T. Honjo, and T. Chiba. 2008. Activation-induced cytidine deaminase links between inflammation and the development of colitis-associated colorectal cancers. Gastroenterology 135: 889-898.e1-3. https://doi.org/10.1053/j.gastro.2008.06.091
  109. Morisawa, T., H. Marusawa, Y. Ueda, A. Iwai, I. M. Okazaki, T. Honjo, and T. Chiba. 2008. Organ-specific profiles of genetic changes in cancers caused by activation-induced cytidine deaminase expression. Int. J. Cancer 123: 2735-2740. https://doi.org/10.1002/ijc.23853
  110. Endo, Y., H. Marusawa, and T. Chiba. 2011. Involvement of activation-induced cytidine deaminase in the development of colitis-associated colorectal cancers. J. Gastroenterol. 46 Suppl 1: 6-10. https://doi.org/10.1007/s00535-010-0326-1
  111. Takai, A., H. Marusawa, Y. Minaki, T. Watanabe, H. Nakase, K. Kinoshita, G. Tsujimoto, and T. Chiba. 2012. Targeting activation-induced cytidine deaminase prevents colon cancer development despite persistent colonic inflammation. Oncogene 31: 1733-1742. https://doi.org/10.1038/onc.2011.352
  112. Morita, S., Y. Matsumoto, Okuyama, K. Ono, Y. Kitamura, A. Tomori, T. Oyama, Y. Amano, Y. Kinoshita, T. Chiba, and H. Marusawa. 2011 Bile acid-induced expression of activation- induced cytidine deaminase during the development of Barrett's oesophageal adenocarcinoma. Carcinogenesis 32: 1706-1712. https://doi.org/10.1093/carcin/bgr194
  113. Shinmura, K., H. Igarashi, M. Goto, H. Tao, H. Yamada, S. Matsuura, M. Tajima, T. Matsuda, A. Yamane, K. Funai, M. Tanahashi, H. Niwa, H. Ogawa, and H. Sugimura. 2011. Aberrant expression and mutation-inducing activity of AID in human lung cancer. Ann. Surg. Oncol. 18: 2084-2092. https://doi.org/10.1245/s10434-011-1568-8
  114. Miyazaki, Y., H. Inoue, K. Kikuchi, K. Ochiai, and K. Kusama. 2012. Activation-induced cytidine deaminase mRNA expression in oral squamous cell carcinoma-derived cell lines is upregulated by inflammatory cytokines. J. Oral. Sci. 54:71-75. https://doi.org/10.2334/josnusd.54.71
  115. Matsumoto. Y., H. Marusawa, K. Kinoshita, Y. Endo, T. Kou, T. Morisawa, T. Azuma, I. M. Okazaki, T. Honjo, and T. Chiba. 2007. Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium. Nat. Med. 13: 470-476. https://doi.org/10.1038/nm1566
  116. Matsumoto, Y., H. Marusawa, K. Kinoshita, Y. Niwa, Y. Sakai, and T. Chiba. 2010. Up-regulation of activation-induced cytidine deaminase causes genetic aberrations at the CDKN2b-CDKN2a in gastric cancer. Gastroenterology 139:1984-1994. https://doi.org/10.1053/j.gastro.2010.07.010
  117. Goto, A., M. Hirahashi, M. Osada, K. Nakamura, T. Yao, M. Tsuneyoshi, R. Takayanagi, and Y. Oda. 2011. Aberrant activation-induced cytidine deaminase expression is associated with mucosal intestinalization in the early stage of gastric cancer. Virchows Arch. 458: 717-724. https://doi.org/10.1007/s00428-011-1086-x

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