Switch junction sequences in PMS2-deficient mice reveal a microhomology-mediated mechanism of Ig class switch recombination

Isotype switching involves a region-specific, nonhomologous recombinational deletion that has been suggested to occur by nonhomologous joining of broken DNA ends. Here, we find increased donor/acceptor homology at switch junctions from PMS2-deficient mice and propose that class switching can occur by microhomology-mediated end-joining. Interestingly, although isotype switching and somatic hypermutation show many parallels, we confirm that PMS2 deficiency has no major effect on the pattern of nucleotide substitutions generated during somatic hypermutation. This finding is in contrast to MSH2 deficiency. With MSH2, the altered pattern of switch recombination and hypermutation suggests parallels in the mechanics of the two processes, whereas the fact that PMS2 deficiency affects only switch recombination may reflect differences in the pathways of break resolution.

[1]  M. Neuberger,et al.  Somatic Hypermutation in the Absence of DNA-Dependent Protein Kinase Catalytic Subunit (DNA-Pkcs) or Recombination-Activating Gene (Rag)1 Activity , 2000, The Journal of experimental medicine.

[2]  T. Honjo,et al.  Class Switch Recombination and Hypermutation Require Activation-Induced Cytidine Deaminase (AID), a Potential RNA Editing Enzyme , 2000, Cell.

[3]  L. Ricciardiello,et al.  Steady-state Regulation of the Human DNA Mismatch Repair System* , 2000, The Journal of Biological Chemistry.

[4]  J. Haber,et al.  The Saccharomyces cerevisiae Msh2 mismatch repair protein localizes to recombination intermediates in vivo. , 2000, Molecular cell.

[5]  W. Edelmann,et al.  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 , 2000, The Journal of experimental medicine.

[6]  A. Kenter.  The Liaison of Isotype Class Switch and Mismatch Repair , 1999, The Journal of experimental medicine.

[7]  R. Kucherlapati,et al.  Reduced Isotype Switching in Splenic B Cells from Mice Deficient in Mismatch Repair Enzymes , 1999, The Journal of experimental medicine.

[8]  U. Storb,et al.  Different Mismatch Repair Deficiencies All Have the Same Effects on Somatic Hypermutation , 1999, The Journal of experimental medicine.

[9]  M. Neuberger,et al.  Deficiency in Msh2 affects the efficiency and local sequence specificity of immunoglobulin class‐switch recombination: parallels with somatic hypermutation , 1999, The EMBO journal.

[10]  T. Manser,et al.  Severe Attenuation of the B Cell Immune Response in Msh2-deficient Mice , 1999, The Journal of experimental medicine.

[11]  Q. Kong,et al.  PMS2-deficiency diminishes hypermutation of a λ1 transgene in young but not older mice , 1999 .

[12]  J. Haber,et al.  The Many Interfaces of Mre11 , 1998, Cell.

[13]  C. Milstein,et al.  Hot spot focusing of somatic hypermutation in MSH2-deficient mice suggests two stages of mutational targeting. , 1998, Immunity.

[14]  F. Delbos,et al.  Mismatch repair deficiency interferes with the accumulation of mutations in chronically stimulated B cells and not with the hypermutation process. , 1998, Immunity.

[15]  F. Alt,et al.  Ku70 Is Required for Late B Cell Development and Immunoglobulin Heavy Chain Class Switching , 1998, The Journal of experimental medicine.

[16]  T. Kunkel,et al.  Altered spectra of hypermutation in antibodies from mice deficient for the DNA mismatch repair protein PMS2. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[17]  T. Paull,et al.  The 3' to 5' exonuclease activity of Mre 11 facilitates repair of DNA double-strand breaks. , 1998, Molecular cell.

[18]  Heikyung Suh,et al.  Ku80 is required for immunoglobulin isotype switching , 1998, The EMBO journal.

[19]  M. Wabl,et al.  Mismatch repair co-opted by hypermutation. , 1998, Science.

[20]  J. Haber,et al.  Role of Saccharomyces cerevisiae Msh2 and Msh3 repair proteins in double-strand break-induced recombination. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[21]  M. Neuberger,et al.  Rapid methods for the analysis of immunoglobulin gene hypermutation: application to transgenic and gene targeted mice. , 1997, Nucleic acids research.

[22]  P. Glazer,et al.  Elevated levels of mutation in multiple tissues of mice deficient in the DNA mismatch repair gene Pms2. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[23]  A. Rolink,et al.  The SCID but Not the RAG-2 Gene Product Is Required for Sμ–Sε Heavy Chain Class Switching , 1996 .

[24]  M. Radman,et al.  Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer , 1995, Cell.

[25]  Jian Yu,et al.  Male mice defective in the DNA mismatch repair gene PMS2 exhibit abnormal chromosome synapsis in meiosis , 1995, Cell.

[26]  G. Hertz,et al.  DNA sequences at immunoglobulin switch region recombination sites. , 1993, Nucleic acids research.

[27]  L. Stanton,et al.  Nucleotide sequence and properties of the murine γ3 immunoglobulin heavy chain gene switch region: implications for successive Cγ gene switching , 1982 .

[28]  Andreas Radbruch,et al.  Developmental and molecular regulation of immunoglobulin class switch recombination. , 1996, Current topics in microbiology and immunology.

[29]  J. Stavnezer.  Antibody class switching. , 1996, Advances in immunology.

[30]  J. Bonfield,et al.  A new DNA sequence assembly program. , 1995, Nucleic acids research.