Enhanced intra-switch region recombination during immunoglobulin class switch recombination in 53BP1-/- B cells.
Immunoglobulin class switch recombination (CSR) is initiated by activation-induced cytidine deaminase (AID), an enzyme that deaminates cytidine residues in single-stranded DNA. U:G mismatches created by AID are processed to produce lesions that recruit and activate DNA damage response proteins including Ataxia-telangiectasia mutated (ATM), histone H2AX, Nijmegen breakage syndrome 1 (Nbs1), and p53 binding protein 1 (53BP1). Among these proteins, absence of 53BP1 produces the most severe impairment of class switching. Here, we demonstrate that AID is targeted normally to switch region DNA and that intra-switch region recombination is enhanced in 53BP1-/- B cells. In addition, Smicro-Sgamma1 switch region junctions cloned from 53BP1-/- B cells show unusual insertions suggestive of failed class switching. Our data are consistent with a role for 53BP1 in stabilizing the synapsis of switch regions during CSR.
Reina-San-Martin
Bernardo
B
Laboratory of Molecular Immunology, Howard Hughes Medical Institute, The Rockefeller University, New York, USA. reinab@igbmc.u-strasbg.fr
Chen
Junjie
J
Nussenzweig
André
A
Nussenzweig
Michel C
MC
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D001483:Base Sequence; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004249:DNA Damage; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis*; D007134:Immunoglobulin Switch Region / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D011995:Recombination, Genetic / Q000276:immunology*; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics; D000071857:Tumor Suppressor p53-Binding Protein 1
D007132:Immunoglobulin Isotypes; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1