Molecular basis of polyadenylated RNA fate determination in the nucleus

Eukaryotic genomes generate a plethora of polyadenylated (pA + ) RNAs, 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 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.