Mechanism and regulation of class switch recombination.
Antibody class switching occurs in mature B cells in response to antigen stimulation and costimulatory signals. It occurs by a unique type of intrachromosomal deletional recombination within special G-rich tandem repeated DNA sequences [called switch, or S, regions located upstream of each of the heavy chain constant (C(H)) region genes, except Cdelta]. The recombination is initiated by the B cell-specific activation-induced cytidine deaminase (AID), which deaminates cytosines in both the donor and acceptor S regions. AID activity converts several dC bases to dU bases in each S region, and the dU bases are then excised by the uracil DNA glycosylase UNG; the resulting abasic sites are nicked by apurinic/apyrimidinic endonuclease (APE). AID attacks both strands of transcriptionally active S regions, but how transcription promotes AID targeting is not entirely clear. Mismatch repair proteins are then involved in converting the resulting single-strand DNA breaks to double-strand breaks with DNA ends appropriate for end-joining recombination. Proteins required for the subsequent S-S recombination include DNA-PK, ATM, Mre11-Rad50-Nbs1, gammaH2AX, 53BP1, Mdc1, and XRCC4-ligase IV. These proteins are important for faithful joining of S regions, and in their absence aberrant recombination and chromosomal translocations involving S regions occur.
Stavnezer
Janet
J
Department of Molecular Genetics and Microbiology, Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, Massachusetts 01655-012, USA. Janet.Stavnezer@umassmed.edu
Guikema
Jeroen E J
JE
Schrader
Carol E
CE
D000818:Animals; D003564:Cytidine Deaminase / Q000378:metabolism; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D007132:Immunoglobulin Isotypes / Q000235:genetics* / Q000276:immunology; D008957:Models, Genetic; D011995:Recombination, Genetic; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D007132:Immunoglobulin Isotypes; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase