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* Department of Molecular Genetics and Microbiology, Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, MA 01655; and
Department of Cell Biology, Albert Einstein Medical College, Bronx, NY 10461
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants AI65639 (to C.E.S.) and AI23283 (to J.S.), by the Irvington Institute Fellowship Program of the Cancer Research Institute (to J.E.J.G.), and by CA76329 (to W.E.).
2 Current address: Department of Medicine, University Medical Center Groningen, Groningen, The Netherlands.
3 Address correspondence and reprint requests to Dr. Janet Stavnezer, Department of Molecular Genetics and Microbiology, Program in Immunology and Virology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655-0122. E-mail address: janet.stavnezer{at}umassmed.edu
4 Abbreviations used in this paper: CSR, class switch recombination; AID, activation-induced cytidine deaminase; cis-CSR, intrachromosome-CSR; DSB, dsDNA break; KO, knockout; LM-PCR, ligation-mediated PCR; MMR, mismatch repair; Msh, Mut S Homolog; S, switch; SSB, ssDNA break; TR, tandem repeat; trans-CSR, trans-chromosomal CSR; WT, wild type.
This article has been cited by other articles:
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  H. Sekine, R. C. Ferreira, Q. Pan-Hammarstrom, L. Hammarstrom, G. S. Gilkeson, and T. W. Behrens Comment on "Reassessment of the Role of Mut S Homolog 5 in Ig Class Switch Recombination Shows Lack of Involvement in cis- and trans-Switching" J. Immunol., April 15, 2009; 182(8): 4495 - 4496. [Full Text] [PDF]
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J. E. J. Guikema, C. E. Schrader, S. P. Baker, W. Edelmann, and J. Stavnezer Response to Comment on "Reassessment of the Role of Mut S Homolog 5 in Ig Class Switch Recombination Shows Lack of Involvement in cis- and trans-Switching" J. Immunol., April 15, 2009; 182(8): 4496 - 4497. [Full Text] [PDF]
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