A nuclear RNA degradation code is recognized by PAXT for eukaryotic transcriptome surveillance.

The RNA exosome plays critical roles in eukaryotic RNA degradation, but how it specifically recognizes its targets remains unclear. The poly(A) tail exosome targeting (PAXT) connection is a nuclear adaptor that recruits the exosome to polyadenylated RNAs, 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 (ss) and a poly(A) junction (PAJ) but not by either sequence alone. These sequences are bound by U1 small nuclear ribonucleoprotein particle (snRNP) and cleavage/polyadenylation factors, which, in turn, cooperatively recruit PAXT. As the 5' ss-PAJ combination is typically absent on correctly processed RNAs, it functions as a "nuclear RNA degradation code" (NRDC). Importantly, disease-associated single nucleotide polymorphisms that create novel 5' ss 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.