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Peer-reviewedCC BYNature

Molecular basis of polyadenylated RNA fate determination in the nucleus

  • Andrii Bugai1,2
  • Ulrich Hohmann3,4,5,6
  • Ana Lorenzo1,2
  • Max Graf5,7,6
  • Laura Fin5,6
  • Jérôme O. Rouvière1,2
  • László Tirián4,8
  • Yuhui Dou1,9,10
  • Marion Le Rest1,2
  • Patrik Polák1,2
  • Dennis Johnsen1,11
  • Lis Jakobsen12,11
4 more authors
  • Jens Andersen12,13
  • Julius Brennecke14,6
  • Clemens Plaschka15,2
  • Torben Heick Jensen16
16 affiliations
  1. 1Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
  2. 2Department of Molecular Biology and Genetics, Aarhus University
  3. 3Institute of Molecular Biology, Mainz, Germany
  4. 4Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Vienna, Austria
  5. 5Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria
  6. 6Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC)
  7. 7Vienna BioCenter PhD Program, Doctoral School of the University of Vienna and Medical University of Vienna, Vienna, Austria
  8. 8Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA)
  9. 9Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
  10. 10Friedrich Miescher Institute for Biomedical Research
  11. 11Department of Biochemistry and Molecular Biology, University of Southern Denmark
  12. 12Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark
  13. 13Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC)
  14. 14Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Vienna, Austria. [email protected]
  15. 15Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria. [email protected]
  16. 16Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark. [email protected]
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{bugai2026molecular,
  title = {{Molecular basis of polyadenylated RNA fate determination in the nucleus}},
  author = {Andrii Bugai and Ulrich Hohmann and Ana Lorenzo and Max Graf and Laura Fin and Jérôme O. Rouvière and László Tirián and Yuhui Dou and Marion Le Rest and Patrik Polák and Dennis Johnsen and Lis Jakobsen and Jens Andersen and Julius Brennecke and Clemens Plaschka and Torben Heick Jensen},
  journal = {Nature},
  year = {2026},
  month = jun,
  doi = {10.1038/s41586-026-10650-0},
  url = {https://doi.org/10.1038/s41586-026-10650-0},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Molecular basis of polyadenylated RNA fate determination in the nucleus
AU  - Andrii Bugai
AU  - Ulrich Hohmann
AU  - Ana Lorenzo
AU  - Max Graf
AU  - Laura Fin
AU  - Jérôme O. Rouvière
AU  - László Tirián
AU  - Yuhui Dou
AU  - Marion Le Rest
AU  - Patrik Polák
AU  - Dennis Johnsen
AU  - Lis Jakobsen
AU  - Jens Andersen
AU  - Julius Brennecke
AU  - Clemens Plaschka
AU  - Torben Heick Jensen
PY  - 2026
DA  - 2026/06/17
JO  - Nature
DO  - 10.1038/s41586-026-10650-0
UR  - https://doi.org/10.1038/s41586-026-10650-0
AB  - 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.
SN  - 0028-0836
SN  - 1476-4687
ER  -