DNA polymerases in adaptive immunity

Nature Reviews Immunology

Volumn 8, Issue 4, 2008, Pages 302-312

  Weill, Jean Claude ^a   Reynaud, Claude Agnès ^a  

^a HÔPITAL NECKER ENFANTS MALADES   (France)

Author keywords

[No Author keywords available]

Indexed keywords

CYCLINE; DNA POLYMERASE; DNA POLYMERASE REV1;

ADAPTIVE IMMUNITY; B LYMPHOCYTE; CELL CYCLE PHASE; CHROMOSOME REPLICATION; DNA RECOMBINATION; DNA STRUCTURE; DNA SYNTHESIS; GENE CONVERSION; GENE MUTATION; HUMAN; MUTAGENESIS; NONHUMAN; PRIORITY JOURNAL; REVIEW; SOMATIC HYPERMUTATION;

EID: 41149153412     PISSN: 14741733     EISSN: None     Source Type: Journal    
DOI: 10.1038/nri2281     Document Type: Review

References (120)

1. Tonegawa, S. Somatic generation of antibody diversity. Nature 302, 575-581 (1983).
2. Rajewsky, K. Clonal selection and learning in the antibody system. Nature 381, 751-758 (1996).
3. Weill, J. C. & Reynaud, C. A. Rearrangement/ hypermutation/gene conversion: when, where and why? Immunol. Today 17, 92-97 (1996).
4. Goodman, M. F. & Tippin, B. The expanding polymerase universe. Nature Rev. Mol. Cell Biol. 1, 101-109 (2000).
5. Burgers, P. M. et al. Eukaryotic DNA polymerases: proposal for a revised nomenclature. J. Biol. Chem. 276, 43487-43490 (2001).
6. Hubscher, U., Maga, G. & Spadari, S. Eukaryotic DNA polymerases. Annu. Rev. Biochem. 71, 133-163 (2002).
7. Friedberg, E. C., Wagner, R. & Radman, M. Specialized DNA polymerases, cellular survival, and the genesis of mutations. Science 296, 1627-1630 (2002).
8. Gellert, M. V(D)J recombination: RAG proteins, repair factors, and regulation. Annu. Rev. Biochem. 71, 101-132 (2002).
9. Schatz, D. G. & Spanopoulou, E. Biochemistry of V(D)J recombination. Curr. Top. Microbiol. Immunol. 290, 49-85 (2005).
10. Revy, P., Malivert, L. & de Villartay, J. P. Cernunnos-XLF, a recently identified non-homologous end-joining factor required for the development of the immune system. Curr. Opin. Allergy Clin. Immunol. 6, 416-420 (2006).
11. Mahajan, K. N., Nick McElhinny, S. A., Mitchell, B. S. & Ramsden, D. A. Association of DNA polymerase μ (polμ) with Ku and ligase IV: role for polμ in end-joining double-strand break repair. Mol. Cell Biol. 22, 5194-5202 (2002).
12. Ma, Y. et al. A biochemically defined system for mammalian nonhomologous DNA end joining. Mol. Cell 16, 701-713 (2004). This paper provides a detailed biochemical analysis of the relative contribution of TdT, Polλ and Polμ to DNA end processing during NHEJ in vitro.
13. Sobol, R. W. & Wilson, S. H. Mammalian DNA β-polymerase in base excision repair of alkylation damage. Prog. Nucleic Acid Res. Mol. Biol. 68, 57-74 (2001).
14. Wilson, T. E. & Lieber, M. R. Efficient processing of DNA ends during yeast nonhomologous end joining. Evidence for a DNA polymerase β (Pol4)-dependent pathway. J. Biol. Chem. 274, 23599-23609 (1999).
15. Aoufouchi, S. et al. Two novel human and mouse DNA polymerases of the polX family. Nucleic Acids Res. 28, 3684-3693 (2000).
16. Dominguez, O. et al. DNA polymerase μ (Polμ), homologous to TdT, could act as a DNA mutator in eukaryotic cells. EMBO J. 19, 1731-1742 (2000).
17. Garcia-Diaz, M. et al. DNA polymerase λ (Polλ), a novel eukaryotic DNA polymerase with a potential role in meiosis. J. Mol. Biol. 301, 851-867 (2000).
18. Lee, J. W. et al. Implication of DNA polymerase λ in alignment-based gap filling for nonhomologous DNA end joining in human nuclear extracts. J. Biol. Chem. 279, 805-811 (2004).
19. Daley, J. M., Laan, R. L., Suresh, A. & Wilson, T. E. DNA joint dependence of pol X family polymerase action in nonhomologous end joining. J. Biol. Chem. 280, 29030-29037 (2005).
20. Nick McElhinny, S. A. et al. A gradient of template dependence defines distinct biological roles for family X polymerases in nonhomologous end joining. Mol. Cell 19, 357-366 (2005).
21. Bertocci, B., De Smet, A., Weill, J. C. & Reynaud, C. A. Nonoverlapping functions of DNA polymerases μ, λ, and terminal deoxynucleotidyltransferase during immunoglobulin V(D)J recombination in vivo. Immunity 25, 31-41 (2006). This paper describes the independent and specific contribution of Polλ and Polμ to heavy-chain and light-chain V(D)J junctions, respectively.
22. Thai, T. H., Purugganan, M. M., Roth, D. B. & Kearney, J. F. Distinct and opposite diversifying activities of terminal transferase splice variants. Nature Immunol. 3, 457-462 (2002).
23. Repasky, J. A., Corbett, E., Boboila, C. & Schatz, D. G. Mutational analysis of terminal deoxynucleotidyltransferase-mediated N-nucleotide addition in V(D)J recombination. J. Immunol. 172, 5478-5488 (2004).
24. Doyen, N., Boule, J. B., Rougeon, F. & Papanicolaou, C. Evidence that the long murine terminal deoxynucleotidyltransferase isoform plays no role in the control of V(D)J junctional diversity. J. Immunol. 172, 6764-6767 (2004).
25. Ma, Y., Pannicke, U., Schwarz, K. & Lieber, M. R. Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination. Cell 108, 781-794 (2002).
26. Moshous, D. et al. Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency. Cell 105, 177-186 (2001).
27. Yang, Y. G., Lindahl, T. & Barnes, D. E. Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell 131, 873-886 (2007).
28. Bertocci, B., De Smet, A., Berek, C., Weill, J. C. & Reynaud, C. A. Immunoglobulin κ light chain gene rearrangement is impaired in mice deficient for DNA polymerase μ. Immunity 19, 203-211 (2003).
29. Tomlinson, I. M., Cox, J. P., Gherardi, E., Lesk, A. M. & Chothia, C. The structural repertoire of the human Vκ domain. EMBO J. 14, 4628-4638 (1995).
30. Lederberg, J. Genes and antibodies. Science 129, 1649-1653 (1959).
31. Burnett, F. The clonal selection theory of acquired immunity (The University Press, Cambridge, 1959).
32. Weigert, M. G., Cesari, I. M., Yonkovich, S. J. & Cohn, M. Variability in the λ light chain sequences of mouse antibody. Nature 228, 1045-1047 (1970).
33. Bothwell, A. L. et al. Heavy chain variable region contribution to the NPb family of antibodies: somatic mutation evident in a γ2a variable region. Cell 24, 625-637 (1981).
34. Gearhart, P. J., Johnson, N. D., Douglas, R. & Hood, L. IgG antibodies to phosphorylcholine exhibit more diversity than their IgM counterparts. Nature 291, 29-34 (1981).
35. Selsing, E. & Storb, U. Somatic mutation of immunoglobulin light-chain variable-region genes. Cell 25, 47-58 (1981).
36. Griffiths, G. M., Berek, C., Kaartinen, M. & Milstein, C. Somatic mutation and the maturation of immune response to 2-phenyl oxazolone. Nature 312, 271-275 (1984).
37. Brenner, S. & Milstein, C. Origin of antibody variation. Nature 211, 242-243 (1966).
38. Muramatsu, M. et al. 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 (1999).
39. Muramatsu, M. et al. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102, 553-563 (2000).
40. Revy, P. et al. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the hyper-IgM syndrome (HIGM2). Cell 102, 565-575 (2000).
41. Di Noia, J. M. & Neuberger, M. S. Molecular mechanisms of antibody somatic hypermutation. Annu. Rev. Biochem. 76, 1-22 (2007).
42. Reynaud, C. A. et al. Mismatch repair and immunoglobulin gene hypermutation: did we learn something? Immunol. Today 20, 522-527 (1999).
43. Martin, A. & Scharff, M. D. AID and mismatch repair in antibody diversification. Nature Rev. Immunol. 2, 605-614 (2002).
44. Martomo, S. A. & Gearhart, P. J. Somatic hypermutation: subverted DNA repair. Curr. Opin. Immunol. 18, 243-248 (2006).
45. Esposito, G. et al. Mice reconstituted with DNA polymerase β-deficient fetal liver cells are able to mount a T cell-dependent immune response and mutate their Ig genes normally. Proc. Natl Acad. Sci. USA 97, 1166-1171 (2000).
46. Prakash, S., Johnson, R. E. & Prakash, L. Eukaryotic translesion synthesis DNA polymerases: specificity of structure and function. Annu. Rev. Biochem. 74, 317-353 (2005).
47. Goodman, M. F. Error-prone repair DNA polymerases in prokaryotes and eukaryotes. Annu. Rev. Biochem. 71, 17-50 (2002).
48. Friedberg, E. C. Suffering in silence: the tolerance of DNA damage. Nature Rev. Mol. Cell Biol. 6, 943-953 (2005).
49. Zhang, Y. et al. Lesion bypass activities of human DNA polymerase μ. J. Biol. Chem. 277, 44582-44587 (2002).
50. Maga, G. et al. 8-oxo-guanine bypass by human DNA polymerases in the presence of auxiliary proteins. Nature 447, 606-608 (2007).
51. Seki, M. et al. High-efficiency bypass of DNA damage by human DNA polymerase Q. EMBO J. 23, 4484-4494 (2004).
52. Masutani, C. et al. The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase η. Nature 399, 700-704 (1999).
53. Johnson, R. E., Kondratick, C. M., Prakash, S. & Prakash, L. hRAD30 mutations in the variant form of xeroderma pigmentosum. Science 285, 263-265 (1999).
54. Zeng, X. et al. DNA polymerase η is an A-T mutator in somatic hypermutation of immunoglobulin variable genes. Nature Immunol. 2, 537-541 (2001). The first demonstration of the contribution of a TLS polymerase to SHM, through the analysis of patients with the XP-V syndrome, a genetic disease caused by a deficiency in Polη activity.
55. Faili, A. et al. DNA polymerase η is involved in hypermutation occurring during immunoglobulin class switch recombination. J. Exp. Med. 199, 265-270 (2004).
56. Delbos, F. et al. Contribution of DNA polymerase η to immunoglobulin gene hypermutation in the mouse. J. Exp. Med. 201, 1191-1196 (2005).
57. Martomo, S. A. et al. Different mutation signatures in DNA polymerase η- and MSH6-deficient mice suggest separate roles in antibody diversification. Proc. Natl Acad. Sci. USA 102, 8656-8661 (2005).
58. Martomo, S. A. et al. Normal hypermutation in antibody genes from congenic mice defective for DNA polymerase ι. DNA Repair (Amst) 5, 392-398 (2006).
59. Matsuda, T. et al. Error rate and specificity of human and murine DNA polymerase ε. J. Mol. Biol. 312, 335-346 (2001).
60. Pavlov, Y. I. et al. Correlation of somatic hypermutation specificity and A-T base pair substitution errors by DNA polymerase ε during copying of a mouse immunoglobulin κ light chain transgene. Proc. Natl Acad. Sci. USA 99, 9954-9959 (2002).
61. Ohashi, E. et al. Fidelity and processivity of DNA synthesis by DNA polymerase κ, the product of the human DINB1 gene. J. Biol. Chem. 275, 39678-39684 (2000).
62. Zhang, Y. et al. Error-free and error-prone lesion bypass by human DNA polymerase κ in vitro. Nucleic Acids Res. 28, 4138-4146 (2000).
63. Schenten, D. et al. DNA polymerase κ deficiency does not affect somatic hypermutation in mice. Eur. J. Immunol. 32, 3152-3160 (2002).
64. Shimizu, T., Shinkai, Y., Ogi, T., Ohmori, H. & Azuma, T. The absence of DNA polymerase κ does not affect somatic hypermutation of the mouse immunoglobulin heavy chain gene. Immunol. Lett. 86, 265-270 (2003).
65. Delbos, F., Aoufouchi, S., Faili, A., Weill, J. C. & Reynaud, C. A. DNA polymerase η is the sole contributor of A/T modifications during immunoglobulin gene hypermutation in the mouse. J. Exp. Med. 204, 17-23 (2007). A paper establishing Polη as the sole contributor of A/T mutations during the normal SHM process in mice, and proposing that the two UNG and MSH2-MSH6 pathways that process uracils are competitive rather than alternative.
66. Nelson, J. R., Lawrence, C. W. & Hinkle, D. C. Deoxycytidyl transferase activity of yeast REV1 protein. Nature 382, 729-731 (1996).
67. Zhang, Y. et al. Response of human REV1 to different DNA damage: preferential dCMP insertion opposite the lesion. Nucleic Acids Res. 30, 1630-1638 (2002).
68. Guo, C. et al. Mouse Rev1 protein interacts with multiple DNA polymerases involved in translesion DNA synthesis. EMBO J. 22, 6621-6630 (2003).
69. Jansen, J. G. et al. The BRCT domain of mammalian Rev1 is involved in regulating DNA translesion synthesis. Nucleic Acids Res. 33, 356-365 (2005).
70. Jansen, J. G. et al. Strand-biased defect in C/G. transversions in hypermutating immunoglobulin genes in Rev1-deficient mice. J. Exp. Med. 203, 319-323 (2006). This paper demonstrates the contribution of Rev1 to G/C transversion mutations, with an unexpected strand bias.
71. Johnson, R. E., Washington, M. T., Haracska, L., Prakash, S. & Prakash, L. Eukaryotic polymerases ι and ζ act sequentially to bypass DNA lesions. Nature 406, 1015-1019 (2000).
72. Esposito, G. et al. Disruption of the Rev3l-encoded catalytic subunit of polymerase ζ in mice results in early embryonic lethality. Curr. Biol. 10, 1221-1224 (2000).
73. Bemark, M., Khamlichi, A. A., Davies, S. L. & Neuberger, M. S. Disruption of mouse polymerase ζ (Rev3) leads to embryonic lethality and impairs blastocyst development in vitro. Curr. Biol. 10, 1213-1216 (2000).
74. Wittschieben, J. et al. Disruption of the developmentally regulated Rev3l gene causes embryonic lethality. Curr. Biol. 10, 1217-1220 (2000).
75. Zhong, X. et al. The fidelity of DNA synthesis by yeast DNA polymerase ζ alone and with accessory proteins. Nucleic Acids Res. 34, 4731-4742 (2006).
76. Diaz, M., Verkoczy, L. K., Flajnik, M. F. & Klinman, N. R. Decreased frequency of somatic hypermutation and impaired affinity maturation but intact germinal center formation in mice expressing antisense RNA to DNA polymerase ζ. J. Immunol. 167, 327-335 (2001).
77. Zan, H. et al. The translesion DNA polymerase ζ plays a major role in Ig and bcl-6 somatic hypermutation. Immunity 14, 643-653 (2001).
78. Tissier, A., McDonald, J. P., Frank, E. G. & Woodgate, R. polι, a remarkably error-prone human DNA polymerase. Genes Dev. 14, 1642-1650 (2000).
79. Frank, E. G. & Woodgate, R. Increased catalytic activity and altered fidelity of human DNA polymerase ι in the presence of manganese. J. Biol. Chem. 282, 24689-24696 (2007).
80. Sale, J. E. & Neuberger, M. S. TdT-accessible breaks are scattered over the immunoglobulin V domain in a constitutively hypermutating B cell line. Immunity 9, 859-869 (1998).
81. Denepoux, S. et al. Induction of somatic mutation in a human B cell line in vitro. Immunity 6, 35-46 (1997).
82. + B cell line in vitro: definition of the requirements and modalities of hypermutation. J. Immunol. 162, 3437-3447 (1999).
83. Faili, A. et al. AID-dependent somatic hypermutation occurs as a DNA single-strand event in the BL2 cell line. Nature Immunol. 3, 815-821 (2002).
84. Xiao, Z. et al. Known components of the immunoglobulin A:T mutational machinery are intact in Burkitt lymphoma cell lines with G:C bias. Mol. Immunol. 44, 2659-2666 (2007).
85. Faili, A. et al. Induction of somatic hypermutation in immunoglobulin genes is dependent on DNA polymerase ι. Nature 419, 944-947 (2002).
86. McDonald, J. P. et al. 129-derived strains of mice are deficient in DNA polymerase ι and have normal immunoglobulin hypermutation. J. Exp. Med. 198, 635-643 (2003).
87. Poltoratsky, V., Prasad, R., Horton, J. K. & Wilson, S. H. Down-regulation of DNA polymerase β accompanies somatic hypermutation in human BL2 cell lines. DNA Repair (Amst) 6, 244-253 (2007).
88. Zan, H. et al. The translesion DNA polymerase θ plays a dominant role in immunoglobulin gene somatic hypermutation. EMBO J. 24, 3757-3769 (2005).
89. Masuda, K. et al. Absence of DNA polymerase θ results in decreased somatic hypermutation frequency and altered mutation patterns in Ig genes. DNA Repair (Amst) 5, 1384-1391 (2006).
90. Masuda, K. et al. DNA polymerases η and θ function in the same genetic pathway to generate mutations at A/T during somatic hypermutation of Ig genes. J. Biol. Chem. 282, 17387-17394 (2007).
91. Masuda, K. et al. DNA polymerase θ contributes to the generation of C/G mutations during somatic hypermutation of Ig genes. Proc. Natl Acad. Sci. USA 102, 13986-13991 (2005).
92. Kannouche, P. L., Wing, J. & Lehmann, A. R. Interaction of human DNA polymerase η with monoubiquitinated PCNA: a possible mechanism for the polymerase switch in response to DNA damage. Mol. Cell 14, 491-500 (2004).
93. Warbrick, E. PCNA binding through a conserved motif. Bioessays 20, 195-199 (1998).
94. Bienko, M. et al. Ubiquitin-binding domains in Y-family polymerases regulate translesion synthesis. Science 310, 1821-1824 (2005).
95. Langerak, P., Nygren, A. O., Krijger, P. H., van den Berk, P. C. & Jacobs, H. A/T mutagenesis in hypermutated immunoglobulin genes strongly depends on PCNAK164 modification. J. Exp. Med. 204, 1989-1998 (2007). This reference provides a demonstration of the major role of PCNA ubiquitylation in the A/T mutation pathway.
96. Moldovan, G. L., Pfander, B. & Jentsch, S. PCNA, the maestro of the replication fork. Cell 129, 665-679 (2007).
97. Rada, C., Di Noia, J. M. & Neuberger, M. S. Mismatch recognition and uracil excision provide complementary paths to both Ig switching and the A/T-focused phase of somatic mutation. Mol. Cell 16, 163-171 (2004). A landmark paper establishing that uracils produced by AID-mediated cytidine deamination are processed by only two pathways, UNG and MSH2-MSH6. The mutations observed in the MSH2 and UNG double-deficient background therefore represent the footprint of AID deamination at the immunoglobulin locus.
98. Rada, C. et al. Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG-deficient mice. Curr. Biol. 12, 1748-1755 (2002).
99. Wiesendanger, M., Kneitz, B., Edelmann, W. & Scharff, M. D. Somatic hypermutation in MutS homologue (MSH)3-, MSH6-, and MSH3/MSH6-deficient mice reveals a role for the MSH2-MSH6 heterodimer in modulating the base substitution pattern. J. Exp. Med. 191, 579-584 (2000).
100. Martomo, S. A., Yang, W. W. & Gearhart, P. J. A role for Msh6 but not Msh3 in somatic hypermutation and class switch recombination. J. Exp. Med. 200, 61-68 (2004).
101. -/- double-knockout mice. J. Immunol. 177, 5386-5392 (2006).
102. Bardwell, P. D. et al. Altered somatic hypermutation and reduced class-switch recombination in exonuclease 1-mutant mice. Nature Immunol. 5, 224-229 (2004).
103. Phung, Q. H., Winter, D. B., Alrefai, R. & Gearhart, P. J. Hypermutation in Ig V genes from mice deficient in the MLH1 mismatch repair protein. J. Immunol. 162, 3121-3124 (1999).
104. Unniraman, S. & Schatz, D. G. Strand-biased spreading of mutations during somatic hypermutation. Science 317, 1227-1230 (2007).
105. Avkin, S., Adar, S., Blander, G. & Livneh, Z. Quantitative measurement of translesion replication in human cells: evidence for bypass of abasic sites by a replicative DNA polymerase. Proc. Natl Acad. Sci. USA 99, 3764-3769 (2002).
106. Zeng, X., Negrete, G. A., Kasmer, C., Yang, W. W. & Gearhart, P. J. Absence of DNA polymerase η reveals targeting of C mutations on the nontranscribed strand in immunoglobulin switch regions. J. Exp. Med. 199, 917-924 (2004).
107. Wu, X. & Stavnezer, J. DNA polymerase β is able to repair breaks in switch regions and plays an inhibitory role during immunoglobulin class switch recombination. J. Exp. Med. 204, 1677-1689 (2007).
108. Buerstedde, J. M. et al. Light chain gene conversion continues at high rate in an ALV-induced cell line. EMBO J. 9, 921-927 (1990).
109. Kim, S., Humphries, E. H., Tjoelker, L., Carlson, L. & Thompson, C. B. Ongoing diversification of the rearranged immunoglobulin light-chain gene in a bursal lymphoma cell line. Mol. Cell Biol. 10, 3224-3231 (1990).
110. Harris, R. S., Sale, J. E., Petersen-Mahrt, S. K. & Neuberger, M. S. AID is essential for immunoglobulin V gene conversion in a cultured B cell line. Curr. Biol. 12, 435-438 (2002).
111. Arakawa, H., Hauschild, J. & Buerstedde, J. M. Requirement of the activation-induced deaminase (AID) gene for immunoglobulin gene conversion. Science 295, 1301-1306 (2002).
112. Arakawa, H., Saribasak, H. & Buerstedde, J. M. Activation-induced cytidine deaminase initiates immunoglobulin gene conversion and hypermutation by a common intermediate. PLoS Biol. 2, E179 (2004).
113. Kawamoto, T. et al. Dual roles for DNA polymerase η in homologous DNA recombination and translesion DNA synthesis. Mol. Cell 20, 793-799 (2005).
114. Reynaud, C. A., Aoufouchi, S., Faili, A. & Weill, J. C. What role for AID: mutator, or assembler of the immunoglobulin mutasome? Nature Immunol. 4, 631-638 (2003).
115. McIlwraith, M. J. et al. Human DNA polymerase η promotes DNA synthesis from strand invasion intermediates of homologous recombination. Mol. Cell 20, 783-792 (2005).
116. Taddei, F. et al. Role of mutator alleles in adaptive evolution. Nature 387, 700-702 (1997).
117. Yeiser, B., Pepper, E. D., Goodman, M. F. & Finkel, S. E. SOS-induced DNA polymerases enhance long-term survival and evolutionary fitness. Proc. Natl Acad. Sci. USA 99, 8737-8741 (2002).
118. Saribasak, H. et al. Uracil DNA glycosylase disruption blocks Ig gene conversion and induces transition mutations. J. Immunol. 176, 365-371 (2006).
119. Simpson, L. J. & Sale, J. E. Rev1 is essential for DNA damage tolerance and non-templated immunoglobulin gene mutation in a vertebrate cell line. EMBO J. 22, 1654-1664 (2003).
120. Arakawa, H. et al. A role for PCNA ubiquitination in immunoglobulin hypermutation. PLoS Biol. 4, e366 (2006).