Mechanisms for antigen receptor gene diversification in lymphocytes. (A) V(D)J recombination is initiated by DNA cleavage at RSS (triangles) bordering variable region gene segments. Rejoining of ends is reciprocal and requires the DNA-PKcs and Ku proteins, as well as XRCC4 and DNA ligase IV. (B) Class switch recombination is targeted by an unknown mechanism involving switch regions located upstream of constant region coding exons. Like V(D)J recombination, rejoining is reciprocal and requires the DNA-PKcs and Ku proteins. (C) Somatic hypermutation is targeted to Ig variable regions by a transcriptional mechanism. DNA breaks occur in the course of the mutation process, which leads to base substitutions as well as small insertions and deletions.