Journal article
Role for Msh5 in the regulation of Ig class switch recombination
Proceedings of the National Academy of Sciences - PNAS, Vol.104(17), pp.7193-7198
04/24/2007
Handle:
https://hdl.handle.net/2376/114677
PMCID: PMC1855370
PMID: 17409188
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/
lpr
mice carrying a congenic H-2
b/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-2
b
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.
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Details
- Title
- Role for Msh5 in the regulation of Ig class switch recombination
- Creators
- Hideharu Sekine - Medical University of South Carolina, Charleston, SC 29425Ricardo C Ferreira - University of Minnesota Medical School, Minneapolis, MN 55455Qiang Pan-Hammarström - Karolinska University Hospital, SE-141 86 Huddinge, SwedenRobert R Graham - Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142Beth Ziemba - University of Minnesota Medical School, Minneapolis, MN 55455Sandra S de Vries - The Netherlands Cancer Institute, 1066 CX, Amsterdam, The NetherlandsJiabin Liu - University of Minnesota Medical School, Minneapolis, MN 55455Keli Hippen - University of Minnesota Medical School, Minneapolis, MN 55455Thearith Koeuth - University of Minnesota Medical School, Minneapolis, MN 55455Ward Ortmann - University of Minnesota Medical School, Minneapolis, MN 55455Akiko Iwahori - Medical University of South Carolina, Charleston, SC 29425Margaret K Elliott - Medical University of South Carolina, Charleston, SC 29425Steven Offer - University of Minnesota Medical School, Minneapolis, MN 55455Cara Skon - University of Minnesota Medical School, Minneapolis, MN 55455Likun Du - Karolinska University Hospital, SE-141 86 Huddinge, SwedenJill Novitzke - University of Minnesota Medical School, Minneapolis, MN 55455Annette T Lee - Feinstein Institute for Medical Research, Manhasset, NY 11030Nianxi Zhao - Washington State University, Pullman, WA 99164Joshua D Tompkins - Washington State University, Pullman, WA 99164David Altshuler - Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142Peter K Gregersen - Feinstein Institute for Medical Research, Manhasset, NY 11030Charlotte Cunningham-Rundles - Mount Sinai School of Medicine, New York, NY 10029; andReuben S Harris - University of Minnesota Medical School, Minneapolis, MN 55455Chengtao Her - Washington State University, Pullman, WA 99164David L Nelson - National Cancer Institute, Bethesda, MD 20892Lennart Hammarström - Karolinska University Hospital, SE-141 86 Huddinge, SwedenGary S Gilkeson - Medical University of South Carolina, Charleston, SC 29425Timothy W Behrens - University of Minnesota Medical School, Minneapolis, MN 55455
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.104(17), pp.7193-7198
- Academic Unit
- Molecular Biosciences, School of; Horticulture, Department of
- Publisher
- National Academy of Sciences
- Identifiers
- 99900547687701842
- Language
- English
- Resource Type
- Journal article