Nonsense-associated altered splicing: a frame-dependent response distinct from nonsense-mediated decay

Nonsense-associated altered splicing (NAS) is a putative correction response that upregulates alternatively spliced transcripts that have skipped offending premature termination codons (PTCs). Here, we examined whether NAS has characteristics in common with nonsense-mediated decay (NMD), a surveillance mechanism that degrades PTC-bearing mRNAs. We discovered that although NAS shared the need for a Kozak AUG to define frame, it differed from NMD. NAS was not affected by depletion of the NMD protein hUPF2, and it functioned independently of RNA stabilization. We identified an alternatively spliced transcript acted upon by both NAS and NMD, indicating that these two mechanisms are not mutually exclusive. Our results suggest that NAS and NMD are distinct mechanisms despite being triggered by the same signal.