Role for Msh5 in the regulation of Ig class switch recombination

Hideharu Sekine, Ricardo C. Ferreira, Qiang Pan-Hammarström, Robert R. Graham, Beth Ziemba, Sandra S. De Vries, Jiabin Liu, Keli Hippen, Thearith Koeuth, Ward Ortmann, Akiko Iwahori, Margaret K. Elliott, Steven Offer, Cara Skon, Likun Du, Jill Novitzke, Annette T. Lee, Nianxi Zhao, Joshua D. Tompkins, David AltshulerPeter K. Gregersen, Charlotte Cunningham-Rundles, Reuben S. Harris, Chengtao Her, David L. Nelson, Lennart Hammarström, Gary S. Gilkeson, Timothy W. Behrens

Research output: Contribution to journalArticlepeer-review

120 Scopus citations

Abstract

Ig class switch recombination (CSR) and somatic hypermutation serve to diversify antibody responses and are orchestrated by the activity of activation-induced cytidine deaminase and many proteins involved in DNA repair and genome surveillance. Msh5, a gene encoded in the central MHC class III region, and its obligate heterodimerization partner Msh4 have a critical role in regulating meiotic homologous recombination and have not been implicated in CSR. Here, we show that MRL/Ipr mice carrying a congenic H-2b/b MHC interval exhibit several abnormalities regarding CSR, including a profound deficiency of IgG3 in most mice and long microhomologies at Ig switch (S) joints. We found that Msh5 is expressed at low levels on the H-2b haplotype and, importantly, a similar long S joint microhomology phenotype was observed in both Msh5 and Msh4-null mice. We also present evidence that genetic variation in MSH5 is associated with IgA deficiency and common variable immune deficiency (CVID) in humans. One of the human MSH5 alleles identified contains two nonsynonymous polymorphisms, and the variant protein encoded by this allele shows impaired binding to MSH4. Similar to the mice, Ig S joints from CVID and IgA deficiency patients carrying disease-associated MSH5 alleles show increased donor/acceptor microhomology, involving pentameric DNA repeat sequences and lower mutation rates than controls. Our findings suggest that Msh4/5 heterodimers contribute to CSR and support a model whereby Msh4/5 promotes the resolution of DNA breaks with low or no terminal microhomology by a classical nonhomologous end-joining mechanism while possibly suppressing an alternative microhomology-mediated pathway.

Original languageEnglish (US)
Pages (from-to)7193-7198
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number17
DOIs
StatePublished - Apr 24 2007

Keywords

  • Immunoglobulin subclass deficiency
  • Mismatch repair
  • Msh4

ASJC Scopus subject areas

  • Genetics
  • General

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