Immunoglobulin genes undergo legitimate repair in human B cells not only after cis- but also frequent trans-class switch recombination.
Immunoglobulin (Ig) genes specifically recruit activation-induced deaminase (AID) for 'on-target' DNA deamination, initiating either variable (V) region somatic hypermutation, or double-strand break intermediates of class switch recombination (CSR). Such breaks overwhelmingly undergo legitimate intra-Ig repair rather than rare illegitimate and potentially oncogenic junctions outside of Ig loci. We show that in human B cells, legitimate synapsis and repair efficiently join Ig genes whether physically linked on one chromosome or located apart on both alleles. This indicates mechanisms faithfully recognizing and/or pairing loci with homology in structure and accessibility, thus licensing interchromosomal trans-CSR junctions while usually preventing illegitimate interchromosomal recombination with AID off-target genes. Physical linkage of IgH genes in cis on the same allele just increases the likelihood of legitimate repair by another fourfold. The strongest force driving CSR might thus be recognition of legitimate target genes. Formation of IgH intra-allelic loops along this process would then constitute a consequence rather than a pre-requisite of this gene-pairing process.
1] Immunology CNRS UMR7276, Limoges, France [2] Université de Limoges, UMR7276, Institut Universitaire de France, Limoges, France.
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Laffleur
1] Immunology CNRS UMR7276, Limoges, France [2] Université de Limoges, UMR7276, Institut Universitaire de France, Limoges, France.
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Bardet
1] Immunology CNRS UMR7276, Limoges, France [2] Université de Limoges, UMR7276, Institut Universitaire de France, Limoges, France.
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Garot
1] Immunology CNRS UMR7276, Limoges, France [2] Hôpital Universitaire Dupuytren, Laboratoire d'Immunologie, Limoges, France.
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Brousse
Immunology CNRS UMR7276, Limoges, France.
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Baylet
1] Immunology CNRS UMR7276, Limoges, France [2] Université de Limoges, UMR7276, Institut Universitaire de France, Limoges, France [3] Hôpital Universitaire Dupuytren, Laboratoire d'Immunologie, Limoges, France.
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D000483:Alleles; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D001483:Base Sequence; D005803:Genes, Immunoglobulin; D006801:Humans; D017578:Immunoglobulin Class Switching; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011995:Recombination, Genetic
D007143:Immunoglobulin Heavy Chains