Home LiteratureArticle Details
PMID: 10662804 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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.

The Journal of experimental medicine ·Vol. 191 ·No. 3 ·2000-02-07 ·Pages 579-84

Wiesendanger M, Kneitz B, Edelmann W, Scharff MD

Abstract

Although the primary function of the DNA mismatch repair (MMR) system is to identify and correct base mismatches that have been erroneously introduced during DNA replication, recent studies have further implicated several MMR components in somatic hypermutation of immunoglobulin (Ig) genes. We studied the immune response in mice deficient in MutS homologue (MSH)3 and MSH6, two mutually exclusive partners of MSH2 that have not been examined previously for their role in Ig hypermutation. In Msh6(-)/- and Msh3(-)/-/Msh6(-)/- mice, base substitutions are preferentially targeted to G and C nucleotides and to an RGYW hot spot, as has been shown previously in Msh2(-)/- mice. In contrast, Msh3(-)/- mice show no differences from their littermate controls. These findings indicate that the MSH2-MSH6 heterodimer, but not the MSH2-MSH3 complex, is responsible for modulating Ig hypermutation.

MeSH Terms
Adenosine Triphosphatases Animals B-Lymphocytes/immunology Bacterial Proteins/genetics Base Pair Mismatch DNA Repair DNA-Binding Proteins/deficiency,genetics Dimerization Escherichia coli Proteins Mice Multidrug Resistance-Associated Proteins MutS DNA Mismatch-Binding Protein MutS Homolog 2 Protein MutS Homolog 3 Protein Mutation Proto-Oncogene Proteins/deficiency Spleen/immunology
Chemicals
Bacterial Proteins DNA-Binding Proteins Escherichia coli Proteins G-T mismatch-binding protein MSH3 protein, human Msh6 protein, mouse Multidrug Resistance-Associated Proteins MutS Homolog 3 Protein Proto-Oncogene Proteins Adenosine Triphosphatases Msh2 protein, mouse MutS DNA Mismatch-Binding Protein MutS Homolog 2 Protein MutS protein, E coli multidrug resistance-associated protein 1
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Wiesendanger M
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Kneitz B
Edelmann W
Scharff M D
References (32)
32 references, click to expand
  1. Evolution of somatic hypermutation and gene conversion in adaptive immunity.
    Immunol Rev. 1998 Apr;162:13-24 PMID: 9602348
  2. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. V. Affinity maturation develops in two stages of clonal selection.
    J Exp Med. 1998 Mar 16;187(6):885-95 PMID: 9500791
  3. Analysis of the targeting of the hypermutational machinery and the impact of subsequent selection on the distribution of nucleotide changes in human VHDJH rearrangements.
    Immunol Rev. 1998 Apr;162:161-71 PMID: 9602362
  4. The role of DNA repair in somatic hypermutation of immunoglobulin genes.
    J Exp Med. 1998 Jun 1;187(11):1729-33 PMID: 9607914
  5. 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
  6. 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
  7. 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
  8. Both DNA strands of antibody genes are hypermutation targets.
    Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8791-4 PMID: 9671757
  9. Mismatch repair deficiency interferes with the accumulation of mutations in chronically stimulated B cells and not with the hypermutation process.
    Immunity. 1998 Jul;9(1):127-34 PMID: 9697842
  10. Hot spot focusing of somatic hypermutation in MSH2-deficient mice suggests two stages of mutational targeting.
    Immunity. 1998 Jul;9(1):135-41 PMID: 9697843
  11. TdT-accessible breaks are scattered over the immunoglobulin V domain in a constitutively hypermutating B cell line.
    Immunity. 1998 Dec;9(6):859-69 PMID: 9881976
  12. Severe attenuation of the B cell immune response in Msh2-deficient mice.
    J Exp Med. 1999 Feb 1;189(3):471-82 PMID: 9927509
  13. Hypermutation in Ig V genes from mice deficient in the MLH1 mismatch repair protein.
    J Immunol. 1999 Mar 15;162(6):3121-4 PMID: 10092760
  14. Somatic hypermutation and the three R's: repair, replication and recombination.
    Mutat Res. 1999 Mar;436(2):157-78 PMID: 10095138
  15. Deficiency in Msh2 affects the efficiency and local sequence specificity of immunoglobulin class-switch recombination: parallels with somatic hypermutation.
    EMBO J. 1999 Jun 15;18(12):3484-90 PMID: 10369687
  16. PMS2-deficiency diminishes hypermutation of a lambda1 transgene in young but not older mice.
    Mol Immunol. 1999 Feb;36(2):83-91 PMID: 10378680
  17. Different mismatch repair deficiencies all have the same effects on somatic hypermutation: intact primary mechanism accompanied by secondary modifications.
    J Exp Med. 1999 Jul 5;190(1):21-30 PMID: 10429667
  18. Reduced isotype switching in splenic B cells from mice deficient in mismatch repair enzymes.
    J Exp Med. 1999 Aug 2;190(3):323-30 PMID: 10430621
  19. Mutation in the mismatch repair gene Msh6 causes cancer susceptibility.
    Cell. 1997 Nov 14;91(4):467-77 PMID: 9390556
  20. The DNA mismatch repair genes Msh3 and Msh6 cooperate in intestinal tumor suppression.
    Cancer Res. 2000 Feb 15;60(4):803-7 PMID: 10706084
  21. Stepwise intraclonal maturation of antibody affinity through somatic hypermutation.
    Proc Natl Acad Sci U S A. 1988 Nov;85(21):8206-10 PMID: 3263647
  22. The repertoire of somatic antibody mutants accumulating in the memory compartment after primary immunization is restricted through affinity maturation and mirrors that expressed in the secondary response.
    J Exp Med. 1990 Dec 1;172(6):1681-9 PMID: 2124253
  23. Mechanisms and biological effects of mismatch repair.
    Annu Rev Genet. 1991;25:229-53 PMID: 1812808
  24. 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
  25. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. III. The kinetics of V region mutation and selection in germinal center B cells.
    J Exp Med. 1993 Oct 1;178(4):1293-307 PMID: 8376935
  26. 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
  27. Biochemistry and genetics of eukaryotic mismatch repair.
    Genes Dev. 1996 Jun 15;10(12):1433-42 PMID: 8666228
  28. Rapid methods for the analysis of immunoglobulin gene hypermutation: application to transgenic and gene targeted mice.
    Nucleic Acids Res. 1997 May 15;25(10):1913-9 PMID: 9115357
  29. The extent of affinity maturation differs between the memory and antibody-forming cell compartments in the primary immune response.
    EMBO J. 1997 Jun 2;16(11):2996-3006 PMID: 9214617
  30. Mismatch repair co-opted by hypermutation.
    Science. 1998 Feb 20;279(5354):1207-10 PMID: 9469811
  31. Frequent occurrence of deletions and duplications during somatic hypermutation: implications for oncogene translocations and heavy chain disease.
    Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2463-8 PMID: 9482908
  32. Amino acid insertions and deletions contribute to diversify the human Ig repertoire.
    Immunol Rev. 1998 Apr;162:143-51 PMID: 9602360
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.191.3.579
Published
2000-02-07
Pages
579-84
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2195810
Subset
IM
Grants
NCI NIH HHS · 5R37CA39838 · United States
NCI NIH HHS · R01CA72649 · United States
NCI NIH HHS · R01CA76329 · United States
External Links
PubMed source DOI: 10.1084/jem.191.3.579 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: product@genelibs.com

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