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PMID: 9607915 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Hypermutation of immunoglobulin genes in memory B cells of DNA repair-deficient mice.

The Journal of experimental medicine ·Vol. 187 ·No. 11 ·1998-06-01 ·Pages 1735-43

Jacobs H, Fukita Y, van der Horst GT, de Boer J, Weeda G, Essers J, de Wind N, Engelward BP, Samson L, Verbeek S, de Murcia JM, de Murcia G, te Riele H, Rajewsky K

Abstract

To investigate the possible involvement of DNA repair in the process of somatic hypermutation of rearranged immunoglobulin variable (V) region genes, we have analyzed the occurrence, frequency, distribution, and pattern of mutations in rearranged Vlambda1 light chain genes from naive and memory B cells in DNA repair-deficient mutant mouse strains. Hypermutation was found unaffected in mice carrying mutations in either of the following DNA repair genes: xeroderma pigmentosum complementation group (XP)A and XPD, Cockayne syndrome complementation group B (CSB), mutS homologue 2 (MSH2), radiation sensitivity 54 (RAD54), poly (ADP-ribose) polymerase (PARP), and 3-alkyladenine DNA-glycosylase (AAG). These results indicate that both subpathways of nucleotide excision repair, global genome repair, and transcription-coupled repair are not required for somatic hypermutation. This appears also to be true for mismatch repair, RAD54-dependent double-strand-break repair, and AAG-mediated base excision repair.

MeSH Terms
Animals B-Lymphocytes/immunology DNA Repair/physiology Gene Rearrangement, B-Lymphocyte Genes, Immunoglobulin Immunoglobulin Variable Region/genetics Immunoglobulin lambda-Chains/genetics Immunologic Memory/immunology Mice Mice, Mutant Strains Mutation Polymerase Chain Reaction
Chemicals
Immunoglobulin Variable Region Immunoglobulin lambda-Chains
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Jacobs H
Basel Institute for Immunology, CH-4005 Basel, Switzerland. [email protected]
Fukita Y
van der Horst G T
de Boer J
Weeda G
Essers J
de Wind N
Engelward B P
Samson L
Verbeek S
de Murcia J M
de Murcia G
te Riele H
Rajewsky K
References (57)
57 references, click to expand
  1. Mutagenesis in mammalian cells induced by triple helix formation and transcription-coupled repair.
    Science. 1996 Feb 9;271(5250):802-5 PMID: 8628995
  2. Increased hypermutation at G and C nucleotides in immunoglobulin variable genes from mice deficient in the MSH2 mismatch repair protein.
    J Exp Med. 1998 Jun 1;187(11):1745-51 PMID: 9607916
  3. Somatic hypermutation of immunoglobulin genes is linked to transcription initiation.
    Immunity. 1996 Jan;4(1):57-65 PMID: 8574852
  4. Somatic hypermutation.
    Curr Opin Immunol. 1995 Apr;7(2):248-54 PMID: 7546385
  5. Increased susceptibility to ultraviolet-B and carcinogens of mice lacking the DNA excision repair gene XPA.
    Nature. 1995 Sep 14;377(6545):169-73 PMID: 7675086
  6. Elements regulating somatic hypermutation of an immunoglobulin kappa gene: critical role for the intron enhancer/matrix attachment region.
    Cell. 1994 Apr 22;77(2):239-48 PMID: 8168132
  7. A new view of V(D)J recombination.
    Genes Cells. 1996 Mar;1(3):269-75 PMID: 9133660
  8. Origin of antibody variation.
    Nature. 1966 Jul 16;211(5046):242-3 PMID: 5965537
  9. Three unusual repair deficiencies associated with transcription factor BTF2(TFIIH): evidence for the existence of a transcription syndrome.
    Cold Spring Harb Symp Quant Biol. 1994;59:317-29 PMID: 7587084
  10. Transcription-coupled repair and human disease.
    Science. 1994 Dec 23;266(5193):1957-8 PMID: 7801121
  11. hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6.
    Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13629-34 PMID: 8942985
  12. Characterization of the cis-acting elements required for somatic hypermutation of murine antibody V genes using conventional transgenic and transgene homologous recombination approaches.
    Semin Immunol. 1996 Jun;8(3):141-50 PMID: 8738913
  13. Hypothesis: somatic hypermutation by gene conversion via the error prone DNA----RNA----DNA information loop.
    Mol Immunol. 1987 Jun;24(6):667-73 PMID: 2443841
  14. Binding of insertion/deletion DNA mismatches by the heterodimer of yeast mismatch repair proteins MSH2 and MSH3.
    Curr Biol. 1996 Sep 1;6(9):1185-7 PMID: 8805366
  15. B lymphocytes of xeroderma pigmentosum or Cockayne syndrome patients with inherited defects in nucleotide excision repair are fully capable of somatic hypermutation of immunoglobulin genes.
    J Exp Med. 1997 Aug 4;186(3):413-9 PMID: 9236193
  16. Might gene conversion be the mechanism of somatic hypermutation of mammalian immunoglobulin genes?
    Trends Genet. 1989 Jan;5(1):4-8 PMID: 2652391
  17. Identical V region amino acid sequences and segments of sequences in antibodies of different specificities. Relative contributions of VH and VL genes, minigenes, and complementarity-determining regions to binding of antibody-combining sites.
    J Immunol. 1991 Sep 1;147(5):1709-19 PMID: 1908882
  18. The dynamic nature of the antibody repertoire.
    Immunol Rev. 1988 Oct;105:5-26 PMID: 3058579
  19. The molecular basis of somatic hypermutation of immunoglobulin genes.
    Curr Opin Immunol. 1996 Apr;8(2):206-14 PMID: 8725944
  20. Analysis of the repertoire of anti-(4-hydroxy-3-nitrophenyl)acetyl (NP) antibodies in C 57 BL/6 mice by cell fusion. II. Characterization of idiotopes by monoclonal anti-idiotope antibodies.
    Eur J Immunol. 1979 Dec;9(12):1004-13 PMID: 398773
  21. Somatic mutation of immunoglobulin lambda chains: a segment of the major intron hypermutates as much as the complementarity-determining regions.
    Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12614-8 PMID: 7809087
  22. ERCC6, a member of a subfamily of putative helicases, is involved in Cockayne's syndrome and preferential repair of active genes.
    Cell. 1992 Dec 11;71(6):939-53 PMID: 1339317
  23. Two pathways for base excision repair in mammalian cells.
    J Biol Chem. 1996 Apr 19;271(16):9573-8 PMID: 8621631
  24. The general transcription-repair factor TFIIH is recruited to the excision repair complex by the XPA protein independent of the TFIIE transcription factor.
    J Biol Chem. 1995 Mar 3;270(9):4896-902 PMID: 7876263
  25. Somatic hypermutation: how many mechanisms diversify V region sequences?
    Cell. 1995 Oct 6;83(1):9-12 PMID: 7553877
  26. Germinal centres in T-cell-dependent antibody responses.
    Immunol Today. 1992 Jan;13(1):17-21 PMID: 1739427
  27. A mouse model for the basal transcription/DNA repair syndrome trichothiodystrophy.
    Mol Cell. 1998 Jun;1(7):981-90 PMID: 9651581
  28. High incidence of ultraviolet-B-or chemical-carcinogen-induced skin tumours in mice lacking the xeroderma pigmentosum group A gene.
    Nature. 1995 Sep 14;377(6545):165-8 PMID: 7675085
  29. Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer.
    Cell. 1995 Jul 28;82(2):321-30 PMID: 7628020
  30. Timing, genetic requirements and functional consequences of somatic hypermutation during B-cell development.
    Immunol Rev. 1987 Apr;96:5-22 PMID: 3298009
  31. Repair-deficient 3-methyladenine DNA glycosylase homozygous mutant mouse cells have increased sensitivity to alkylation-induced chromosome damage and cell killing.
    EMBO J. 1996 Feb 15;15(4):945-52 PMID: 8631315
  32. Zonal distribution of immunoglobulin-synthesizing cells within the germinal centre: an in situ hybridization and immunohistochemical study.
    J Pathol. 1990 Nov;162(3):209-16 PMID: 2125071
  33. Somatic diversification of immunoglobulin heavy chain VDJ genes: evidence for somatic gene conversion in rabbits.
    Cell. 1990 Nov 30;63(5):987-97 PMID: 2124176
  34. Distribution of mutations around rearranged heavy-chain antibody variable-region genes.
    Mol Cell Biol. 1990 Oct;10(10):5187-96 PMID: 2118991
  35. The 5' boundary of somatic hypermutation in a V kappa gene is in the leader intron.
    Eur J Immunol. 1994 Jun;24(6):1453-7 PMID: 8206104
  36. Rabbit IgH sequences in appendix germinal centers: VH diversification by gene conversion-like and hypermutation mechanisms.
    Immunity. 1994 Nov;1(8):647-59 PMID: 7600292
  37. A mutation in the XPB/ERCC3 DNA repair transcription gene, associated with trichothiodystrophy.
    Am J Hum Genet. 1997 Feb;60(2):320-9 PMID: 9012405
  38. The efficiency of antibody affinity maturation: can the rate of B-cell division be limiting?
    Immunol Today. 1990 Sep;11(9):305-8 PMID: 2206275
  39. Requirement of mammalian DNA polymerase-beta in base-excision repair.
    Nature. 1996 Jan 11;379(6561):183-6 PMID: 8538772
  40. Somatic hypermutation occurs in B cells of terminal deoxynucleotidyl transferase-, CD23-, interleukin-4-, IgD- and CD30-deficient mouse mutants.
    Eur J Immunol. 1996 Aug;26(8):1966-9 PMID: 8765046
  41. Clonal selection and learning in the antibody system.
    Nature. 1996 Jun 27;381(6585):751-8 PMID: 8657279
  42. Disruption of mouse RAD54 reduces ionizing radiation resistance and homologous recombination.
    Cell. 1997 Apr 18;89(2):195-204 PMID: 9108475
  43. Introduction: what mechanism(s) drive hypermutation?
    Semin Immunol. 1996 Jun;8(3):125-9 PMID: 8738911
  44. Defective transcription-coupled repair in Cockayne syndrome B mice is associated with skin cancer predisposition.
    Cell. 1997 May 2;89(3):425-35 PMID: 9150142
  45. Somatic hypermutation of Ig genes in patients with xeroderma pigmentosum (XP-D).
    Int Immunol. 1996 May;8(5):701-5 PMID: 8671657
  46. It was a very good year for DNA repair.
    Cell. 1994 Jan 14;76(1):1-4 PMID: 8287470
  47. Analysis of individual immunoglobulin lambda light chain genes amplified from single cells is inconsistent with variable region gene conversion in germinal-center B cell somatic mutation.
    Eur J Immunol. 1994 Aug;24(8):1816-22 PMID: 8056040
  48. Mapping the upstream boundary of somatic mutations in rearranged immunoglobulin transgenes and endogenous genes.
    Mol Immunol. 1994 Feb;31(2):83-98 PMID: 8309480
  49. Analysis of sequence transfers resembling gene conversion in a mouse antibody transgene.
    Science. 1994 Sep 9;265(5178):1590-3 PMID: 8079173
  50. Generation of antibody diversity in the immune response of BALB/c mice to influenza virus hemagglutinin.
    Proc Natl Acad Sci U S A. 1984 May;81(10):3180-4 PMID: 6203114
  51. The mechanism of somatic hypermutation studied with transgenic and transfected target genes.
    Semin Immunol. 1996 Jun;8(3):131-40 PMID: 8738912
  52. Generation of immunoglobulin variable gene diversity.
    Immunol Today. 1982 Apr;3(4):107-12 PMID: 25291455
  53. Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells.
    Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7303-7 PMID: 9207086
  54. Isolation of an hMSH2-p160 heterodimer that restores DNA mismatch repair to tumor cells.
    Science. 1995 Jun 30;268(5219):1909-12 PMID: 7604264
  55. Direct association between the yeast Rad51 and Rad54 recombination proteins.
    J Biol Chem. 1996 Dec 27;271(52):33181-6 PMID: 8969173
  56. Mutation pattern of immunoglobulin transgenes is compatible with a model of somatic hypermutation in which targeting of the mutator is linked to the direction of DNA replication.
    EMBO J. 1991 Dec;10(13):4331-41 PMID: 1756738
  57. A hyperconversion mechanism generates the chicken light chain preimmune repertoire.
    Cell. 1987 Feb 13;48(3):379-88 PMID: 3100050
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
Published
1998-06-01
Pages
1735-43
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2212309
Subset
IM
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