Gene X ppt(Gene10 基因十)--Chapter18.ppt

18.7 H Chains Are Assembled by Two Sequential Recombination Events 18.8 Recombination Generates Extensive Diversity 18.11 Allelic Exclusion Is Triggered by Productive Rearrangements V(D)J gene rearrangement is productive if it leads to expression of a protein. A productive V(D)J gene rearrangement prevents any further rearrangement of the same kind from occurring, whereas a nonproductive rearrangement does not. Allelic exclusion applies separately to L chains (only one κ or λ may be productively rearranged) and to H chains (one H chain is productively rearranged). FIGURE 16: Allelic exclusion limits successful rearrangement to one allele 18.12 RAG1/RAG2 Catalyze Breakage and Religation of V(D)J Gene Segments The RAG proteins are necessary and sufficient for the cleavage reaction. RAG1 recognizes the nonamer consensus sequences for recombination. RAG2 binds to RAG1 and cleaves DNA at the heptamer. The reaction resembles the topoisomerase-like resolution reaction that occurs in transposition. FIGURE 17: Diversity is generated during V-C joining 18.12 RAG1/RAG2 Catalyze Breakage and Religation of V(D)J Gene Segments The reaction proceeds through a hairpin intermediate at the coding end; opening of the hairpin is responsible for insertion of extra bases (P nucleotides) in the recombined gene. Terminal deoxynucleotidyl transferase (TdT) inserts additional unencoded N nucleotides at the V(D)J junctions. The DSBs at the coding joints are repaired by the same mechanism that has generated the whole V(D)J sequence. 18.12 RAG1/RAG2 Catalyze Breakage and Religation of V(D)J Gene Segments severe combined immunodeficiency (SCID) – A syndrome that stems from mutations in different genes that result in B and/or T cell deficiency. X-linked SCID is due to IL-2R γ chain gene mutations; autosomal recessive SCID can be due to RAG1/RAG2 mutations, Artemis gene mutations, Jak3 gene mutations, ADA gene mutations, IL-7R α-chain mutations, CD3 δ or ε mutations, or CD45 gene mutati