Molecular basis of polyadenylated RNA fate determination in the nucleus

Eukaryotic genomes generate a plethora of polyadenylated (pA ⁺ ) RNAs ^1,2 , that are packaged into ribonucleoprotein particles (RNPs). To ensure faithful gene expression, functional pA ⁺ RNPs, including protein-coding RNPs, are exported to the cytoplasm, while transcripts within non-functional pA ⁺ RNPs are degraded in the nucleus ^1–4 . How cells distinguish these opposing fates remains unknown. The DExD-box ATPase UAP56/DDX39B is a central component of functional pA ⁺ RNPs, promoting their docking to the nuclear pore complex (NPC)-anchored ‘transcription and export complex 2 (TREX-2)’ (ref. ^5,6 ), which triggers transcript release from UAP56 to facilitate export (ref. ^7,8 ). Here, we uncover that the ‘Poly(A) tail exosome targeting (PAXT)’ connection ⁹ harbors its own TREX-2-like module, which releases pA ⁺ RNAs from UAP56 for decay by the nuclear exosome. The core of this module consists of a LENG8-PCID2-SEM1 (LENG8-PS) trimer, which we show is structurally and functionally equivalent to the central GANP-PCID2-SEM1 (GANP-PS) trimer of TREX-2. Mutagenesis and transcriptomic data demonstrate that the nuclear fate of pA ⁺ RNPs is governed by the contending actions of nucleoplasmic PAXT and NPC-associated TREX-2, which interpret RNA-bound UAP56 as a signal for RNA decay or export, respectively. As RNA targets of PAXT are generally short and intron-poor, we propose an overall model for pA ⁺ RNP fate determination, whereby the distinct sub-nuclear localizations of PAXT and TREX-2 govern the degradation of short non-functional pA ⁺ RNAs while allowing export of their longer and functional counterparts.