Home LiteratureArticle Details
PMID: 9607916 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Increased hypermutation at G and C nucleotides in immunoglobulin variable genes from mice deficient in the MSH2 mismatch repair protein.

The Journal of experimental medicine ·Vol. 187 ·No. 11 ·1998-06-01 ·Pages 1745-51

Phung QH, Winter DB, Cranston A, Tarone RE, Bohr VA, Fishel R, Gearhart PJ

Abstract

Rearranged immunoglobulin variable genes are extensively mutated after stimulation of B lymphocytes by antigen. Mutations are likely generated by an error-prone DNA polymerase, and the mismatch repair pathway may process the mispairs. To examine the role of the MSH2 mismatch repair protein in hypermutation, Msh2-/- mice were immunized with oxazolone, and B cells were analyzed for mutation in their VkappaOx1 light chain genes. The frequency of mutation in the repair-deficient mice was similar to that in Msh2+/+ mice, showing that MSH2-dependent mismatch repair does not cause hypermutation. However, there was a striking bias for mutations to occur at germline G and C nucleotides. The results suggest that the hypermutation pathway frequently mutates G.C pairs, and a MSH2-dependent pathway preferentially corrects mismatches at G and C.

MeSH Terms
Animals Base Composition Base Sequence Cytosine DNA Repair DNA-Binding Proteins Gene Deletion Gene Rearrangement, B-Lymphocyte Guanine Immunoglobulin Variable Region/genetics Immunoglobulin kappa-Chains/genetics Mice Mice, Inbred C57BL Molecular Sequence Data MutS Homolog 2 Protein Mutation Nucleic Acid Heteroduplexes Oxazolone/immunology Proto-Oncogene Proteins/deficiency,genetics,physiology
Chemicals
DNA-Binding Proteins Immunoglobulin Variable Region Immunoglobulin kappa-Chains Nucleic Acid Heteroduplexes Proto-Oncogene Proteins Oxazolone Guanine Cytosine Msh2 protein, mouse MutS Homolog 2 Protein
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Phung Q H
Laboratory of Molecular Genetics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
Winter D B
Cranston A
Tarone R E
Bohr V A
Fishel R
Gearhart P J
References (41)
41 references, click to expand
  1. Origin of antibody variation.
    Nature. 1966 Jul 16;211(5046):242-3 PMID: 5965537
  2. 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
  3. Clusters of point mutations are found exclusively around rearranged antibody variable genes.
    Proc Natl Acad Sci U S A. 1983 Jun;80(11):3439-43 PMID: 6222379
  4. mRNA sequences define an unusually restricted IgG response to 2-phenyloxazolone and its early diversification.
    Nature. 1983 Jul 28-Aug 3;304(5924):320-4 PMID: 6877353
  5. Relationship of germinal centers in lymphoid tissue to immunologic memory. VI. Transfer of B cell memory with lymph node cells fractionated according to their receptors for peanut agglutinin.
    J Immunol. 1983 Nov;131(5):2254-7 PMID: 6605381
  6. Hydroxylation of deoxyguanosine at the C-8 position by ascorbic acid and other reducing agents.
    Nucleic Acids Res. 1984 Feb 24;12(4):2137-45 PMID: 6701097
  7. Somatic mutation and the maturation of immune response to 2-phenyl oxazolone.
    Nature. 1984 Nov 15-21;312(5991):271-5 PMID: 6504141
  8. Patterns of somatic mutations in immunoglobulin variable genes.
    Genetics. 1987 Jan;115(1):169-76 PMID: 3557109
  9. Three-dimensional structure determination of an anti-2-phenyloxazolone antibody: the role of somatic mutation and heavy/light chain pairing in the maturation of an immune response.
    EMBO J. 1990 Dec;9(12):3807-14 PMID: 2123450
  10. Kinetics of oxidized cytosine repair by endonuclease III of Escherichia coli.
    Biochemistry. 1997 Jul 15;36(28):8628-33 PMID: 9214309
  11. Cells strongly expressing Ig(kappa) transgenes show clonal recruitment of hypermutation: a role for both MAR and the enhancers.
    EMBO J. 1997 Jul 1;16(13):3987-94 PMID: 9233808
  12. Mutator phenotype in Msh2-deficient murine embryonic fibroblasts.
    Cancer Res. 1997 Sep 1;57(17):3765-71 PMID: 9288785
  13. Female embryonic lethality in mice nullizygous for both Msh2 and p53.
    Nat Genet. 1997 Sep;17(1):114-8 PMID: 9288110
  14. Augmented expression of a human gene for 8-oxoguanine DNA glycosylase (MutM) in B lymphocytes of the dark zone in lymph node germinal centers.
    J Exp Med. 1997 Nov 3;186(9):1547-56 PMID: 9348312
  15. Somatic hypermutation introduces insertions and deletions into immunoglobulin V genes.
    J Exp Med. 1998 Jan 5;187(1):59-70 PMID: 9419211
  16. Tissues of MSH2-deficient mice demonstrate hypermutability on exposure to a DNA methylating agent.
    Proc Natl Acad Sci U S A. 1998 Feb 3;95(3):1126-30 PMID: 9448296
  17. Mismatch repair co-opted by hypermutation.
    Science. 1998 Feb 20;279(5354):1207-10 PMID: 9469811
  18. Somatic mutation in ectothermic vertebrates: musings on selection and origins.
    Curr Top Microbiol Immunol. 1998;229:199-216 PMID: 9479856
  19. Hypermutation of immunoglobulin genes in memory B cells of DNA repair-deficient mice.
    J Exp Med. 1998 Jun 1;187(11):1735-43 PMID: 9607915
  20. Altered spectra of hypermutation in antibodies from mice deficient for the DNA mismatch repair protein PMS2.
    Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6953-8 PMID: 9618520
  21. DNA replication fidelity.
    J Biol Chem. 1992 Sep 15;267(26):18251-4 PMID: 1526964
  22. Somatic hypermutagenesis in immunoglobulin genes. II. Influence of neighbouring base sequences on mutagenesis.
    Biochim Biophys Acta. 1992 Nov 15;1171(1):11-8 PMID: 1420357
  23. What limits affinity maturation of antibodies in Xenopus--the rate of somatic mutation or the ability to select mutants?
    EMBO J. 1992 Dec;11(12):4337-47 PMID: 1425571
  24. Instability and decay of the primary structure of DNA.
    Nature. 1993 Apr 22;362(6422):709-15 PMID: 8469282
  25. Clues to the pathogenesis of familial colorectal cancer.
    Science. 1993 May 7;260(5109):812-6 PMID: 8484121
  26. Somatic variation precedes extensive diversification of germline sequences and combinatorial joining in the evolution of immunoglobulin heavy chain diversity.
    J Exp Med. 1993 Sep 1;178(3):815-24 PMID: 8350055
  27. Defective mismatch repair in extracts of colorectal and endometrial cancer cell lines exhibiting microsatellite instability.
    J Biol Chem. 1994 May 20;269(20):14367-70 PMID: 8182040
  28. 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
  29. Locus-specific somatic hypermutation in germinal centre T cells.
    Nature. 1994 Dec 8;372(6506):556-9 PMID: 7990929
  30. Mismatch repair deficiency in phenotypically normal human cells.
    Science. 1995 May 5;268(5211):738-40 PMID: 7632227
  31. Isolation of an hMSH2-p160 heterodimer that restores DNA mismatch repair to tumor cells.
    Science. 1995 Jun 30;268(5219):1909-12 PMID: 7604264
  32. GTBP, a 160-kilodalton protein essential for mismatch-binding activity in human cells.
    Science. 1995 Jun 30;268(5219):1912-4 PMID: 7604265
  33. 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
  34. MSH2 deficient mice are viable and susceptible to lymphoid tumours.
    Nat Genet. 1995 Sep;11(1):64-70 PMID: 7550317
  35. An immunoglobulin mutator that targets G.C base pairs.
    Proc Natl Acad Sci U S A. 1996 Jan 23;93(2):851-5 PMID: 8570647
  36. Di- and trinucleotide target preferences of somatic mutagenesis in normal and autoreactive B cells.
    J Immunol. 1996 Apr 1;156(7):2642-52 PMID: 8786330
  37. Differences in the spectrum of spontaneous mutations in the hprt gene between tumor cells of the microsatellite mutator phenotype.
    Mutat Res. 1996 May;316(5-6):249-59 PMID: 8649458
  38. Somatic hypermutation of immunoglobulin genes.
    Annu Rev Immunol. 1996;14:441-57 PMID: 8962691
  39. Affinity maturation without germinal centres in lymphotoxin-alpha-deficient mice.
    Nature. 1996 Aug 1;382(6590):462-6 PMID: 8684487
  40. Mismatch repair in replication fidelity, genetic recombination, and cancer biology.
    Annu Rev Biochem. 1996;65:101-33 PMID: 8811176
  41. Molecular basis of base substitution hotspots in Escherichia coli.
    Nature. 1978 Aug 24;274(5673):775-80 PMID: 355893
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.187.11.1745
Published
1998-06-01
Pages
1745-51
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2212314
Subset
IM
Grants
NCI NIH HHS · R01 CA067007 · United States
NCI NIH HHS · CA-56542 · United States
NCI NIH HHS · CA-67007 · United States
External Links
PubMed source DOI: 10.1084/jem.187.11.1745 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2