Boundary‐independent polar nonsense‐mediated decay

Nonsense‐mediated decay (NMD) is an RNA surveillance mechanism that degrades mRNAs containing premature termination (nonsense) codons. The second signal for this pathway in mammalian cells is an intron that must be at least ∼55 nucleotides downstream of the nonsense codon. Although the functional significance of this ‘−55 boundary rule’ is not known, it is widely thought to reflect the important role of an exon junction protein complex deposited just upstream of exon–exon junctions after RNA splicing. Here we report that a T‐cell receptor (TCR)‐β gene did not conform to this rule. Rather than a definitive boundary position, nonsense codons had a polar effect, such that nonsense codons distant from the terminal downstream intron triggered robust NMD and proximal nonsense codons caused modest NMD. We identified a region of the TCR‐β gene that conferred this boundary‐independent polar expression pattern on a heterologous gene. Collectively, our results suggest that TCR‐β transcripts contain one or more sequence elements that elicit an unusual NMD response triggered by a novel second signal that ultimately causes boundary‐independent polar regulation. TCR genes may have evolved this unique NMD response because they frequently acquire nonsense codons during normal development.

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