Role for Msh5 in the regulation of Ig class switch recombination.
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.
Sekine
Hideharu
H
Medical University of South Carolina, Charleston, SC 29425, USA.
Ferreira
Ricardo C
RC
Pan-Hammarström
Qiang
Q
Graham
Robert R
RR
Ziemba
Beth
B
de Vries
Sandra S
SS
Liu
Jiabin
J
Hippen
Keli
K
Koeuth
Thearith
T
Ortmann
Ward
W
Iwahori
Akiko
A
Elliott
Margaret K
MK
Offer
Steven
S
Skon
Cara
C
Du
Likun
L
Novitzke
Jill
J
Lee
Annette T
AT
Zhao
Nianxi
N
Tompkins
Joshua D
JD
Altshuler
David
D
Gregersen
Peter K
PK
Cunningham-Rundles
Charlotte
C
Harris
Reuben S
RS
Her
Chengtao
C
Nelson
David L
DL
Hammarström
Lennart
L
Gilkeson
Gary S
GS
Behrens
Timothy W
TW
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
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; C118481:MSH5 protein, human; C512847:Msh5 protein, mouse; D012333:RNA, Messenger