Reassessment of the role of Mut S homolog 5 in Ig class switch recombination shows lack of involvement in cis- and trans-switching

Jeroen E.J. Guikema, Carol E. Schrader, Niek G.J. Leus, Anna Ucher, Erin K. Linehan, Uwe Werling, Winfried Edelmann, Janet Stavnezer

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12 Scopus citations

Abstract

When B cells are activated after immunization or infection, they exchange the gene encoding the Ig H chain C region by class switch recombination (CSR). CSR generally occurs by an intrachromosomal deletional recombination within switch (S) region sequences. However, ∼10% of CSR events occur between chromosome homologs (trans- or interallele CSR), suggesting that the homologous chromosomes are aligned during CSR. Because the Mut S homolog 4 (Msh4) and Msh5 bind to Holliday junctions and are required for homologous recombination during meiosis in germ cells, we hypothesized these proteins might be involved in trans-chromosomal CSR (trans-CSR). Indeed, Msh4-Msh5 has recently been suggested to have a role in CSR. However, we find a large variety of alternative splice variants of Msh5 mRNA in splenic B cells rather than the full-length form found in testis. Most of these mRNAs are unlikely to be stable, suggesting that Msh5 might not be functional. Furthermore, we find that msh5 nullizygous B cells undergo CSR normally, have unaltered levels of trans-CSR, normal levels of DNA breaks in the Sμ region, and normal S-S junctions. We also show that the S-S junctions from cis- and trans-CSR events have similar lengths of junctional microhomology, suggesting trans-CSR occurs by nonhomologous end joining as does intrachromosome (cis)-CSR. From these data, we conclude that Msh5 does not participate in CSR.

Original languageEnglish (US)
Pages (from-to)8450-8459
Number of pages10
JournalJournal of Immunology
Volume181
Issue number12
DOIs
Publication statusPublished - Dec 15 2008

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Guikema, J. E. J., Schrader, C. E., Leus, N. G. J., Ucher, A., Linehan, E. K., Werling, U., ... Stavnezer, J. (2008). Reassessment of the role of Mut S homolog 5 in Ig class switch recombination shows lack of involvement in cis- and trans-switching. Journal of Immunology, 181(12), 8450-8459. https://doi.org/10.4049/jimmunol.181.12.8450