Polζ ablation in B cells impairs the germinal center reaction, class switch recombination, DNA break repair, and genome stability

Journal of Experimental Medicine

Volumn 206, Issue 2, 2009, Pages 477-490

  Schenten, Dominik ^a,b,f   Kracker, Sven ^a,b   Esposito, Gloria ^c,g   Franco, Sonia ^a,b,d   Klein, Ulf ^c,h   Murphy, Michael ^a   Alt, Frederick W ^a,b,d,e   Rajewsky, Klaus ^a,b,c  

^a CENTER FOR BLOOD RESEARCH   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

^c UNIVERSITY OF COLOGNE   (Germany)

^d BOSTON CHILDREN S HOSPITAL   (United States)

^e HOWARD HUGHES MEDICAL INSTITUTE   (United States)

^f YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^g TaconicArtemis   (Germany)

^h Och Spine at New York Presbyterian Hospitals   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

IMMUNOGLOBULIN HEAVY CHAIN; DNA DIRECTED DNA POLYMERASE; DNA POLYMERASE ZETA; PRIMER DNA; REV3 PROTEIN, MOUSE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; B LYMPHOCYTE; CELL MUTANT; CELL PROLIFERATION; CHROMOSOMAL INSTABILITY; CONTROLLED STUDY; DNA REPAIR; DNA STRAND BREAKAGE; DOUBLE STRANDED DNA BREAK; ENZYME ACTIVE SITE; GENOMIC INSTABILITY; GERMINAL CENTER; MOUSE; NONHUMAN; POL ZETA GENE; PRIORITY JOURNAL; SOMATIC HYPERMUTATION; SOMATIC MUTATION; STRUCTURAL GENE; ANIMAL; CHROMOSOME ANALYSIS; COMPARATIVE STUDY; FLOW CYTOMETRY; FLUORESCENCE MICROSCOPY; GENE REARRANGEMENT; GENETICS; IMMUNOLOGY;

ANIMALS; B-LYMPHOCYTES; CHROMOSOMAL INSTABILITY; CYTOGENETIC ANALYSIS; DNA PRIMERS; DNA REPAIR; DNA-DIRECTED DNA POLYMERASE; FLOW CYTOMETRY; GERMINAL CENTER; IMMUNOGLOBULIN CLASS SWITCHING; MICE; MICROSCOPY, FLUORESCENCE; SOMATIC HYPERMUTATION, IMMUNOGLOBULIN;

EID: 63049129975     PISSN: 00221007     EISSN: 15409538     Source Type: Journal    
DOI: 10.1084/jem.20080669     Document Type: Article

References (62)

1. Rajewsky, K. 1996. Clonal selection and learning in the antibody system. Nature. 381:751-758.
2. McKean, D., K. Huppi, M. Bell, L. Staudt, W. Gerhard, and M. Weigert. 1984. Generation of antibody diversity in the immune response of BALB/c mice to influenza virus hemagglutinin. Proc. Natl. Acad. Sci. USA. 81:3180-3184.
3. Kocks, C., and K. Rajewsky. 1988. Stepwise intraclonal maturation of antibody affinity through somatic hypermutation. Proc. Natl. Acad. Sci. USA. 85:8206-8210.
4. Manis, J.P., M. Tian, and F.W. Alt. 2002. Mechanism and control of class-switch recombination. Trends Immunol. 23:31-39.
5. 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.
6. 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.
7. Neuberger, M.S., R.S. Harris, J. Di Noia, and S.K. Petersen-Mahrt. 2003. Immunity through DNA deamination. Trends Biochem. Sci. 28:305-312.
8. Rada, C., G.T. Williams, H. Nilsen, D.E. Barnes, T. Lindahl, and M.S. Neuberger. 2002. Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG-deficient mice. Curr. Biol. 12:1748-1755.
9. Imai, K., G. Slupphaug, W.I. Lee, P. Revy, S. Nonoyama, N. Catalan, L. Yel, M. Forveille, B. Kavli, H.E. Krokan, et al. 2003. Human uracil- DNA glycosylase deficiency associated with profoundly impaired immu- noglobulin class-switch recombination. Nat. Immunol. 4:1023-1028.
10. Revy, P., T. Muto, Y. Levy, F. Geissmann, A. Plebani, O. Sanal, N. Catalan, M. Forveille, R. Dufourcq- Labelouse, A. Gennery, et al. 2000. Activation- induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper- IgM syndrome (HIGM2). Cell. 102:565-575.
11. Schrader, C.E., E.K. Linehan, S.N. Mochegova, R.T. Woodland, and J. Stavnezer. 2005. Inducible DNA breaks in Ig S regions are dependent on AID and UNG. J. Exp. Med. 202:561-568.
12. Guikema, J.E., E.K. Linehan, D. Tsuchimoto, Y. Nakabeppu, P.R. Strauss, J. Stavnezer, and C.E. Schrader. 2007. APE1- and APE2-de- pendent DNA breaks in immunoglobulin class switch recombination. J. Exp. Med. 204:3017-3026.
13. Petersen, S., R. Casellas, B. Reina-San-Martin, H.T. Chen, M.J. Difilippantonio, P.C. Wilson, L. Hanitsch, A. Celeste, M. Muramatsu, D.R. Pilch, et al. 2001. AID is required to initiate Nbs1/gamma- H2AX focus formation and mutations at sites of class switching. Nature. 414:660-665.
14. Rada, C., J. M. Di Noia, and M.S. Neuberger. 2004. 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.
15. Schrader, C.E., J. Vardo, and J. Stavnezer. 2002. Role for mismatch repair proteins Msh2, Mlh1, and Pms2 in immunoglobulin class switching shown by sequence analysis of recombination junctions. J. Exp. Med. 195:367-373.
16. Chaudhuri, J., U. Basu, A. Zarrin, C. Yan, S. Franco, T. Perlot, B. Vuong, J. Wang, R.T. Phan, A. Datta, et al. 2007. Evolution of the im- munoglobulin heavy chain class switch recombination mechanism. Adv. Immunol. 94:157-214.
17. Rooney, S., J. Chaudhuri, and F.W. Alt. 2004. The role of the non-homologous end-joining pathway in lymphocyte development. Immunol. Rev. 200:115-131.
18. Schrader, C.E., J. Vardo, and J. Stavnezer. 2003. Mlh1 can function in antibody class switch recombination independently of Msh2. J. Exp. Med. 197:1377-1383.
19. Ehrenstein, M.R., C. Rada, A.M. Jones, C. Milstein, and M.S. Neuberger. 2001. Switch junction sequences in PMS2-deficient mice reveal a microhomology -mediated mechanism of Ig class switch recombination. Proc. Natl. Acad. Sci. USA. 98:14553-14558.
20. Bardwell, P.D., C.J. Woo, K. Wei, Z. Li, A. Martin, S.Z. Sack, T. Parris, W. Edelmann, and M.D. Scharff. 2004. Altered somatic hyper- mutation and reduced class-switch recombination in exonuclease 1-mu- tant mice. Nat. Immunol. 5:224-229.
21. Kracker, S., Y. Bergmann, I. Demuth, P.O. Frappart, G. Hildebrand, R. Christine, Z.Q. Wang, K. Sperling, M. Digweed, and A. Radbruch. 2005. Nibrin functions in Ig class-switch recombination. Proc. Natl. Acad. Sci. USA. 102:1584-1589.
22. Reina-San-Martin, B., M.C. Nussenzweig, A. Nussenzweig, and S. Difilippantonio. 2005. Genomic instability, endoreduplication, and diminished Ig class-switch recombination in B cells lacking Nbs1. Proc. Natl. Acad. Sci. USA. 102:1590-1595.
23. Yan, C.T., C. Boboila, E.K. Souza, S. Franco, T.R. Hickernell, M. Murphy, S. Gumaste, M. Geyer, A.A. Zarrin, J.P. Manis, et al. 2007. IgH class switching and translocations use a robust non-classical end- joining pathway. Nature. 449:478-482.
24. Reina-San-Martin, B., S. Difilippantonio, L. Hanitsch, R.F. Masilamani, A. Nussenzweig, and M.C. Nussenzweig. 2003. H2AX is required for recombination between immunoglobulin switch regions but not for intra-switch region recombination or somatic hypermutation. J. Exp. Med. 197:1767-1778.
25. Reina-San-Martin, B., H.T. Chen, A. Nussenzweig, and M.C. Nussenzweig. 2004. ATM is required for efficient recombination between immunoglobulin switch regions. J. Exp. Med. 200:1103-1110.
26. Franco, S., M. Gostissa, S. Zha, D.B. Lombard, M.M. Murphy, A.A. Zarrin, C. Yan, S. Tepsuporn, J.C. Morales, M.M. Adams, et al. 2006. H2AX prevents DNA breaks from progressing to chromosome breaks and translocations. Mol. Cell. 21:201-214.
27. Ramiro, A.R., M. Jankovic, E. Callen, S. Difilippantonio, H.T. Chen, K.M. McBride, T.R. Eisenreich, J. Chen, R.A. Dickins, S.W. Lowe, et al. 2006. Role of genomic instability and p53 in AID-induced c-myc- Igh translocations. Nature. 440:105-109.
28. Manis, J. P., J. C. Morales, Z. Xia, J. L. Kutok, F.W. Alt, and P.B. Carpenter. 2004. 53BP1 links DNA damage-response pathways to im- munoglobulin heavy chain class-switch recombination. Nat. Immunol. 5:481-487.
29. Delbos, F., A. De Smet, A. Faili, S. Aoufouchi, J.C. Weill, and C.A. Reynaud. 2005. Contribution of DNA polymerase η to immunoglobulin gene hypermutation in the mouse. J. Exp. Med. 201:1191-1196.
30. Bertocci, B., A. De Smet, E. Flatter, A. Dahan, J.C. Bories, C. Landreau, J.C. Weill, and C.A. Reynaud. 2002. Cutting edge: DNA polymerases mu and lambda are dispensable for Ig gene hypermutation. J. Immunol. 168:3702-3706.
31. Faili, A., S. Aoufouchi, E. Flatter, Q. Gueranger, C.A. Reynaud, and J.C. Weill. 2002. Induction of somatic hypermutation in immunoglobu- lin genes is dependent on DNA polymerase iota. Nature. 419:944-947.
32. Schenten, D., V.L. Gerlach, C. Guo, S. Velasco-Miguel, C.L. Hladik, C.L. White, E.C. Friedberg, K. Rajewsky, and G. Esposito. 2002. DNA polymerase kappa deficiency does not affect somatic hypermutation in mice. Eur. J. Immunol. 32:3152-3160.
33. Esposito, G., G. Texido, U.A. Betz, H. Gu, W. Muller, U. Klein, and K. Rajewsky. 2000. Mice reconstituted with DNA polymerase beta- 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.
34. Masuda, K., R. Ouchida, A. Takeuchi, T. Saito, H. Koseki, K. Kawamura, M. Tagawa, T. Tokuhisa, T. Azuma, and J. O-Wang. 2005. DNA polymerase theta contributes to the generation of C/G mutations during somatic hypermutation of Ig genes. Proc. Natl. Acad. Sci. USA. 102:13986-13991.
35. Zan, H., N. Shima, Z. Xu, A. Al-Qahtani, A.J. Evinger Iii, Y. Zhong, J.C. Schimenti, and P. Casali. 2005. The translesion DNA polymerase theta plays a dominant role in immunoglobulin gene somatic hypermu- tation. EMBO J. 24:3757-3769.
36. J ohnson, R.E., M.T. Washington, L. Haracska, S. Prakash, and L. Prakash. 2000. Eukaryotic polymerases iota and zeta act sequentially to bypass DNA lesions. Nature. 406:1015-1019.
37. Diaz, M., L.K. Verkoczy, M.F. Flajnik, and N.R. Klinman. 2001. Decreased frequency of somatic hypermutation and impaired affinity maturation but intact germinal center formation in mice expressing an- tisense RNA to DNA polymerase zeta. J. Immunol. 167:327-335.
38. Zan, H., A. Komori, Z. Li, A. Cerutti, A. Schaffer, M.F. Flajnik, M. Diaz, and P. Casali. 2001. The translesion DNA polymerase zeta plays a major role in Ig and bcl-6 somatic hypermutation. Immunity. 14:643-653.
39. Bemark, M., A.A. Khamlichi, S.L. Davies, and M.S. Neuberger. 2000. Disruption of mouse polymerase zeta (Rev3) leads to embryonic lethality and impairs blastocyst development in vitro. Curr. Biol. 10:1213-1216.
40. Esposito, G., I. Godindagger, U. Klein, M.L. Yaspo, A. Cumano, and K. Rajewsky. 2000. Disruption of the Rev3l-encoded catalytic subunit of polymerase zeta in mice results in early embryonic lethality. Curr. Biol. 10:1221-1224.
41. Wittschieben, J., M.K. Shivji, E. Lalani, M.A. Jacobs, F. Marini, P.J. Gearhart, I. Rosewell, G. Stamp, and R.D. Wood. 2000. Disruption of the developmentally regulated Rev3l gene causes embryonic lethality. Curr. Biol. 10:1217-1220.
42. Gan, G.N., J. P. Wittschieben, B.O. Wittschieben, and R.D. Wood. 2008. DNA polymerase zeta (pol zeta) in higher eukaryotes. Cell Res. 18:174-183.
43. Van Sloun, P.P., R.J. Romeijn, and J.C. Eeken. 1999. Molecular cloning, expression and chromosomal localisation of the mouse Rev3l gene, encoding the catalytic subunit of polymerase zeta. Mutat. Res. 433:109-116.
44. Kraus, M., M.B. Alimzhanov, N. Rajewsky, and K. Rajewsky. 2004. Survival of resting mature B lymphocytes depends on BCR signaling via the Igalpha/ beta heterodimer. Cell. 117:787-800.
45. Schwenk, F., U. Baron, and K. Rajewsky. 1995. A cre-transgenic mouse strain for the ubiquitous deletion of loxP- flanked gene segments including deletion in germ cells. Nucleic Acids Res. 23:5080-5081.
46. Jolly, C.J., N. Klix, and M.S. Neuberger. 1997. Rapid methods for the analysis of immunoglobulin gene hypermutation: application to trans- genic and gene targeted mice. Nucleic Acids Res. 25:1913-1919.
47. Rush, J.S., M. Liu, V.H. Odegard, S. Unniraman, and D.G. Schatz. 2005. Expression of activation-induced cytidine deaminase is regulated by cell division, providing a mechanistic basis for division-linked class switch recombination. Proc. Natl. Acad. Sci. USA. 102:13242-13247.
48. Zeng, X., G.A. Negrete, C. Kasmer, W.W. Yang, and P.J. Gearhart. 2004. Absence of DNA polymerase i reveals targeting of C mutations on the nontranscribed strand in immunoglobulin switch regions. J. Exp. Med. 199:917-924.
49. Faili, A., S. Aoufouchi, S. Weller, F. Vuillier, A. Stary, A. Sarasin, C.A. Reynaud, and J.C. Weill. 2004. DNA polymerase i is involved in hy- permutation occurring during immunoglobulin class switch recombination. J. Exp. Med. 199:265-270.
50. Schrader, C.E., S.P. Bradley, J. Vardo, S.N. Mochegova, E. Flanagan, and J. Stavnezer. 2003. Mutations occur in the Ig S mu region but rarely in Sgamma regions prior to class switch recombination. EMBO J. 22:5893-5903.
51. Wittschieben, J.P., S.C. Reshmi, S.M. Gollin, and R.D. Wood. 2006. Loss of DNA polymerase zeta causes chromosomal instability in mammalian cells. Cancer Res. 66:134-142.
52. Sonoda, E., T. Okada, G.Y. Zhao, S. Tateishi, K. Araki, M. Yamaizumi, T. Yagi, N.S. Verkaik, D.C. van Gent, M. Takata, and S. Takeda. 2003. Multiple roles of Rev3, the catalytic subunit of polzeta in maintaining genome stability in vertebrates. EMBO J. 22:3188-3197.
53. Callen, E., M. Jankovic, S. Difilippantonio, J.A. Daniel, H.T. Chen, A. Celeste, M. Pellegrini, K. McBride, D. Wangsa, A.L. Bredemeyer, et al. 2007. ATM prevents the persistence and propagation of chromosome breaks in lymphocytes. Cell. 130:63-75.
54. Bemark, M., J.E. Sale, H.J. Kim, C. Berek, R.A. Cosgrove, and M.S. Neuberger. 2000. Somatic hypermutation in the absence of DNA-de- pendent protein kinase catalytic subunit (DNA-PKcs) or recombination-activating gene (RAG)1 activity. J. Exp. Med. 192:1509-1514.
55. Delbos, F., S. Aoufouchi, A. Faili, J.C. Weill, and C.A. Reynaud. 2007. DNA polymerase η is the sole contributor of A/T modifications during im- munoglobulin gene hypermutation in the mouse. J. Exp. Med. 204:17-23.
56. Schrader, C.E., J.E. Guikema, E.K. Linehan, E. Selsing, and J. Stavnezer. 2007. Activation-induced cytidine deaminase-dependent DNA breaks in class switch recombination occur during G1 phase of the cell cycle and depend upon mismatch repair. J. Immunol. 179:6064-6071.
57. Chen, X., K. Kinoshita, and T. Honjo. 2001. Variable deletion and duplication at recombination junction ends: implication for staggered double-strand cleavage in class-switch recombination. Proc. Natl. Acad. Sci. USA. 98:13860-13865.
58. Rush, J.S., S.D. Fugmann, and D.G. Schatz. 2004. Staggered AID-dependent DNA double strand breaks are the predominant DNA lesions targeted to S mu in Ig class switch recombination. Int. Immunol. 16:549-557.
59. Hirano, Y., and K. Sugimoto. 2006. ATR homolog Mec1 controls association of DNA polymerase zeta-Rev1 complex with regions near a double-strand break. Curr. Biol. 16:586-590.
60. Sabbioneda, S., I. Bortolomai, M. Giannattasio, P. Plevani, and M. Muzi-Falconi. 2007. Yeast Rev1 is cell cycle regulated, phosphorylated in response to DNA damage and its binding to chromosomes is dependent upon MEC1. DNA Repair (Amst.). 6:121-127.
61. Mahajan, K.N., S.A. Nick McElhinny, B.S. Mitchell, and D.A. Ramsden. 2002. Association of DNA polymerase mu (pol mu) with Ku and ligase IV: role for pol mu in end-joining double-strand break repair. Mol. Cell. Biol. 22:5194-5202.
62. Fan, W., and X. Wu. 2004. DNA polymerase lambda can elongate on DNA substrates mimicking non-homologous end joining and interact with XRCC4-ligase IV complex. Biochem. Biophys. Res. Commun. 323:1328-1333.