Role for DNA repair factor XRCC4 in immunoglobulin class switch recombination.
V(D)J recombination and immunoglobulin class switch recombination (CSR) are two somatic rearrangement mechanisms that proceed through the introduction of double-strand breaks (DSBs) in DNA. Although the DNA repair factor XRCC4 is essential for the resolution of DNA DSB during V(D)J recombination, its role in CSR has not been established. To bypass the embryonic lethality of XRCC4 deletion in mice, we developed a conditional XRCC4 knockout (KO) using LoxP-flanked XRCC4 cDNA lentiviral transgenesis. B lymphocyte restricted deletion of XRCC4 in these mice lead to an average two-fold reduction in CSR in vivo and in vitro. Our results connect XRCC4 and the nonhomologous end joining DNA repair pathway to CSR while reflecting the possible use of an alternative pathway in the repair of CSR DSB in the absence of XRCC4. In addition, this new conditional KO approach should be useful in studying other lethal mutations in mice.
Soulas-Sprauel
Pauline
P
Institut National de la Santé et de la Recherche Médicale Unité 768, F-75015 Paris, France.
Le Guyader
Gwenaël
G
Rivera-Munoz
Paola
P
Abramowski
Vincent
V
Olivier-Martin
Christelle
C
Goujet-Zalc
Cécile
C
Charneau
Pierre
P
de Villartay
Jean-Pierre
JP
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D005804:Genes, Lethal; D017578:Immunoglobulin Class Switching; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation
D004268:DNA-Binding Proteins; C101467:XRCC4 protein, human; C511788:XRCC4 protein, mouse