Impaired induction of DNA lesions during immunoglobulin class-switch recombination in humans influences end-joining repair.
Ig class-switch recombination (CSR) is a region-specific process that exchanges the constant Ig heavy-chain region and thus modifies an antibody's effector function. DNA lesions in switch (S) regions are induced by activation-induced cytidine deaminase (AID) and uracil-DNA glycosylase 2 (UNG2), subsequently processed to DNA breaks, and resolved by either the classical nonhomologous end-joining pathway or the alternative end-joining pathway (XRCC4/DNA ligase 4- and/or Ku70/Ku80-independent and prone to increased microhomology usage). We examined whether the induction of DNA lesions influences DNA end-joining during CSR by analyzing Sμ-Sα recombination junctions in various human Ig CSR defects of DNA lesion induction. We observed a progressive trend toward the usage of microhomology in Sμ-Sα recombination junctions from AID-heterozygous to AID-autosomal dominant to UNG2-deficient B lymphocytes. We thus hypothesize that impaired induction of DNA lesions in S regions during CSR leads to unusual end-processing of the DNA breaks, resulting in microhomology-mediated end-joining, which could be an indication for preferential processing by alternative end-joining rather than by classical nonhomologous end-joining.
Institut National de la Santé et de la Recherche Médicale U768, Hôpital Necker Enfants Malades, 75015 Paris, France.
Sven
S
Kracker
Kohsuke
K
Imai
Pauline
P
Gardès
Hans D
HD
Ochs
Alain
A
Fischer
Anne H
AH
Durandy
D034961:Antigens, Nuclear / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003564:Cytidine Deaminase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053960:DNA Breaks; D045647:DNA Glycosylases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000502:physiology*; D000072200:Ku Autoantigen; D008297:Male; D011995:Recombination, Genetic / Q000502:physiology*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; C101467:XRCC4 protein, human; D004247:DNA; C492570:CCNO protein, human; D045647:DNA Glycosylases; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen