A nuclear RNA degradation code for eukaryotic transcriptome surveillance

The RNA exosome plays critical roles in eukaryotic RNA degradation, but it remains unclear how the exosome specifically recognizes its targets. The PAXT connection is an adaptor that recruits the exosome to polyadenylated RNAs in the nucleus, especially transcripts polyadenylated at intronic poly(A) sites. Here we show that PAXT-mediated RNA degradation is induced by the combination of a 5' splice site and a poly(A) junction, but not by either sequence alone. These sequences are bound by U1 snRNP and cleavage/polyadenylation factors, which in turn cooperatively recruit PAXT. As the 5' splice site-poly(A) junction combination is typically not found on correctly processed full-length RNAs, we propose that it functions as a "nuclear RNA degradation code" (NRDC). Importantly, disease-associated single nucleotide polymorphisms that create novel 5' splice sites in 3' untranslated regions can induce aberrant mRNA degradation via the NRDC mechanism. Together our study identified the first NRDC, revealed its recognition mechanism, and characterized its role in human diseases.