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PYM1 limits non-canonical Exon Junction Complex occupancy in a gene architecture dependent manner to tune mRNA expression

Author

Listed:
  • Manu Sanjeev

    (The Ohio State University
    The Ohio State University)

  • Lauren A. Woodward

    (The Ohio State University)

  • Michael L. Schiff

    (The Ohio State University)

  • Robert D. Patton

    (The Ohio State University)

  • Sean Myers

    (The Ohio State University)

  • Debadrita Paul

    (The Ohio State University
    The Ohio State University)

  • Ralf Bundschuh

    (The Ohio State University
    The Ohio State University
    The Ohio State University
    The Ohio State University)

  • Guramrit Singh

    (The Ohio State University
    The Ohio State University)

Abstract

The Exon Junction Complex (EJC) decorates RNA exon-exon junctions and modulates mRNA fate at multiple post-transcriptional steps until its disassembly during translation. Our investigation of the EJC disassembly factor PYM1 in human embryonic kidney 293 (HEK293) cells show that the EJC-PYM1 interaction is required for translation-independent EJC destabilization but not for translation-dependent disassembly. Surprisingly, PYM1 interaction deficient EJCs are enriched on locations away from canonical EJC binding site, particularly on transcripts with no or few introns. Such non-canonical EJCs are capable of inducing nonsense-mediated mRNA decay when present downstream of stop codons. Suppression of PYM1 in human cells, including by previously reported PYM1-flavivirus capsid protein interaction, stabilizes mRNAs with fewer and longer exons that localize to endoplasmic reticulum associated TIS-granules. In summary, PYM1 limits non-canonical EJC and thereby acts as an EJC specificity factor that is hijacked by flaviviruses to reshape host cell mRNA regulation.

Suggested Citation

  • Manu Sanjeev & Lauren A. Woodward & Michael L. Schiff & Robert D. Patton & Sean Myers & Debadrita Paul & Ralf Bundschuh & Guramrit Singh, 2025. "PYM1 limits non-canonical Exon Junction Complex occupancy in a gene architecture dependent manner to tune mRNA expression," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63455-6
    DOI: 10.1038/s41467-025-63455-6
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