title: Role for Msh5 in the regulation of Ig class switch recombination.
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.
authors.affiliation: Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Hideharu
authors.initials: H
authors.lastname: Sekine
authors.forename: Ricardo C
authors.initials: RC
authors.lastname: Ferreira
authors.forename: Qiang
authors.initials: Q
authors.lastname: Pan-Hammarström
authors.forename: Robert R
authors.initials: RR
authors.lastname: Graham
authors.forename: Beth
authors.initials: B
authors.lastname: Ziemba
authors.forename: Sandra S
authors.initials: SS
authors.lastname: de Vries
authors.forename: Jiabin
authors.initials: J
authors.lastname: Liu
authors.forename: Keli
authors.initials: K
authors.lastname: Hippen
authors.forename: Thearith
authors.initials: T
authors.lastname: Koeuth
authors.forename: Ward
authors.initials: W
authors.lastname: Ortmann
authors.forename: Akiko
authors.initials: A
authors.lastname: Iwahori
authors.forename: Margaret K
authors.initials: MK
authors.lastname: Elliott
authors.forename: Steven
authors.initials: S
authors.lastname: Offer
authors.forename: Cara
authors.initials: C
authors.lastname: Skon
authors.forename: Likun
authors.initials: L
authors.lastname: Du
authors.forename: Jill
authors.initials: J
authors.lastname: Novitzke
authors.forename: Annette T
authors.initials: AT
authors.lastname: Lee
authors.forename: Nianxi
authors.initials: N
authors.lastname: Zhao
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Tompkins
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Charlotte
authors.initials: C
authors.lastname: Cunningham-Rundles
authors.forename: Reuben S
authors.initials: RS
authors.lastname: Harris
authors.forename: Chengtao
authors.initials: C
authors.lastname: Her
authors.forename: David L
authors.initials: DL
authors.lastname: Nelson
authors.forename: Lennart
authors.initials: L
authors.lastname: Hammarström
authors.forename: Gary S
authors.initials: GS
authors.lastname: Gilkeson
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Behrens
mesh_terms: D000483:Alleles; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017074:Common Variable Immunodeficiency / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004198:Disease Susceptibility; D005786:Gene Expression Regulation; D006239:Haplotypes; D006801:Humans; D017098:IgA Deficiency / Q000235:genetics; D017578:Immunoglobulin Class Switching / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood; D051379:Mice; D020297:Mice, Congenic; D019463:Mice, Inbred MRL lpr; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic / Q000276:immunology*; D013548:Sweden; D014481:United States
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; C118481:MSH5 protein, human; C512847:Msh5 protein, mouse; D012333:RNA, Messenger