Reassessment of the Role of Mut S Homolog 5 in Ig Class Switch Recombination Shows Lack of Involvement in cis- and trans-Switching1

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...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of immunology (1950) 2008-12, Vol.181 (12), p.8450-8459
Main Authors: Guikema, Jeroen E. J., Schrader, Carol E., Leus, Niek G. J., Ucher, Anna, Linehan, Erin K., Werling, Uwe, Edelmann, Winfried, Stavnezer, Janet
Format: Article
Language:English
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 S μ 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.
ISSN:0022-1767
1550-6606