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Fig. 1. Abundance of nonproductive V(D)J rearrangements in B-lineage cells. (A) Schematic representation of productive and nonproductive V(D)J rearrangements during the generation of primary antibody repertoire. V(D)J recombination is initiated by a monoallelic V to DJ recombination at the IgH locus (biallelic D–J rearrangements are not depicted). If successful, then V to J recombination occurs at Ig light chain (IgL) loci. Successive IgL rearrangements are possible due to the fact that there are two Igκ and two Igλ alleles (not depicted). Pre-B cell receptor (pre-BCR) or BCR-mediated feedback signalling upon in-frame rearrangement of one IgH or IgL allele (i.e., VDJ+ or VJ+) prevents V(D)J recombination on the second allele (32). By contrast, a nonproductive V(D)J recombination on one Ig allele (i.e. VDJ− or VJ−) induces rearrangement on the second allele. The imprecise nature of V(D)J junctions generates ~1/3 of productive and ~2/3 of nonproductive V(D)J-rearranged alleles. Hence, most B-lineage cells harbour nonproductively-recombined Ig alleles in their genome (red parts in pie charts). If the two attempts on both Ig alleles are unsuccessful, the cell is programmed to die by apoptosis (dashed circles). (B) PTCs introduced during the error-prone V(D)J recombination process (red stars) or by somatic hypermutations (SHM; yellow stars) can activate different modes of NMD degradation. Frameshift V(D)J junctions can lead to the appearance of PTCs in the variable (V) exon or in the downstream adjacent constant exon. SHM can lead to the appearance of PTCs in the first leader exon (L1: L-part1) or in the V exon, with a greater abundance in the complement-determining regions (CDRs). For IgH mRNAs, PTC introduced by SHM or during V(D)J recombination can elicit exon junction complex (EJC)-dependent NMD. EJCs that remain bound to mRNAs after a pioneer round of translation are depicted (blue ovals). As good NMD candidates, PTC-containing IgH mRNAs are strongly degraded by NMD (up to 100-fold) (1, 9, 59). However, it has been demonstrated that some nonsense codons in the 5′-half of the VDJ exon could not elicit strong NMD degradation (73). Similarly, PTCs close to the initiation codon are NMD resistant in other models likely due to a critical interaction between PABPC1 with the translation initiation complex (74, 75). For nonproductive Igκ alleles, PTCs are located at the end of the V exon or within the last constant Cκ exon. Hence, these PTC-containing IgL mRNAs could not elicit EJC-dependent NMD degradation, although they are likely to be targeted by a PTC-PABC1 distance-dependent mode of NMD which induces a less efficient degradation (~2-fold) (5).
BMB Reports 2019;52:671~678 https://doi.org/10.5483/BMBRep.2019.52.12.232
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