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
DOI: 10.1073/pnas.0700815104
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.
Details
- Title: Subtitle
- Role for Msh5 in the regulation of Ig class switch recombination
- Creators
- Hideharu Sekine - Medical University of South CarolinaRicardo C. Ferreira - University of Minnesota Medical CenterQiang Pan-Hammarström - Karolinska University HospitalRobert R. Graham - Broad InstituteBeth Ziemba - University of Minnesota Medical CenterSandra S. de Vries - Oncode InstituteJiabin Liu - University of Minnesota Medical CenterKeli Hippen - University of Minnesota Medical CenterThearith Koeuth - University of Minnesota Medical CenterWard Ortmann - University of Minnesota Medical CenterAkiko Iwahori - Medical University of South CarolinaMargaret K. Elliott - Medical University of South CarolinaSteven Offer - University of Minnesota Medical CenterCara Skon - University of Minnesota Medical CenterLikun Du - Karolinska University HospitalJill Novitzke - University of Minnesota Medical CenterAnnette T. Lee - Feinstein Institute for Medical ResearchNianxi Zhao - Washington State UniversityJoshua D. Tompkins - Washington State UniversityDavid Altshuler - Broad InstitutePeter K. Gregersen - Feinstein Institute for Medical ResearchCharlotte Cunningham-RundlesReuben S. Harris - University of Minnesota Medical CenterChengtao Her - Washington State UniversityDavid L. Nelson - National Cancer InstituteLennart Hammarström - Karolinska University HospitalGary S. Gilkeson - Medical University of South CarolinaTimothy W. Behrens - University of Minnesota Medical Center
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.104(17), pp.7193-7198
- DOI
- 10.1073/pnas.0700815104
- PMID
- 17409188
- PMCID
- PMC1855370
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Language
- English
- Date published
- 04/24/2007
- Academic Unit
- Pathology
- Record Identifier
- 9984618511402771
Metrics
7 Record Views