RNA surveillance down-regulates expression of nonfunctional κ alleles and detects premature termination within the last κ exon

L Delpy, C Sirac, E Magnoux… - Proceedings of the …, 2004 - National Acad Sciences
L Delpy, C Sirac, E Magnoux, S Duchez, M Cogné
Proceedings of the National Academy of Sciences, 2004National Acad Sciences
Random V (D) J junctions would generate nonfunctional and/or out-of-frame sequences in
about two-thirds of cases and result in abundant transcripts encoding truncated proteins.
Although allelic exclusion at the DNA recombination level ensures that a single allele is
functional, the frequent biallelic rearrangements need additional mechanisms to down-
regulate aberrant transcripts in those cells with both a functionally and a nonfunctionally
rearranged allele. The process of nonsense-mediated decay targets aberrantly rearranged …
Random V(D)J junctions would generate nonfunctional and/or out-of-frame sequences in about two-thirds of cases and result in abundant transcripts encoding truncated proteins. Although allelic exclusion at the DNA recombination level ensures that a single allele is functional, the frequent biallelic rearrangements need additional mechanisms to down-regulate aberrant transcripts in those cells with both a functionally and a nonfunctionally rearranged allele. The process of nonsense-mediated decay targets aberrantly rearranged Ig heavy-chain transcripts, but the situation of light-chain mRNAs is more complex, because they do not meet the usual requirements for nonsense-mediated decay and most often lack a spliceable intron downstream of the premature termination. We studied immunoglobulin heavy-chain -/- pro-B cells in which light chain genes get rearranged and expressed in the absence of any selection for the assembly of a functional B cell receptor. Using this model, we show that the whole κ locus is accessible in pro-B cells and allows the assembly of a broad spectrum of VκJκ segments, most of which are out-of-frame. This model provides an evaluation of the in vivo efficiency of RNA surveillance toward aberrant κ mRNAs produced in pro-B cells. Our data show that nonfunctional κ transcripts are excluded from the mature mRNA pool not only by detecting termination in an upstream exon but also by detecting changes in the position of termination within the last exon. Similar mechanisms efficiently down-regulate nonfunctional κ transcripts arising in normal mature B cells due to the biallelic transcription of rearranged κ genes.
National Acad Sciences