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Regulation of stress granule maturation and dynamics by poly(ADP-ribose) interaction with PARP13

Author

Listed:
  • Shang-Jung Cheng

    (Johns Hopkins University)

  • Temitope Gafaar

    (Johns Hopkins University)

  • Jijin R. A. Kuttiyatveetil

    (Université de Montréal)

  • Aleksandr Sverzhinsky

    (Université de Montréal)

  • Carla Chen

    (Johns Hopkins University)

  • Minghui Xu

    (Johns Hopkins University)

  • Allison Lilley

    (Johns Hopkins University)

  • John M. Pascal

    (Université de Montréal)

  • Anthony K. L. Leung

    (Johns Hopkins University
    Johns Hopkins University
    Johns Hopkins University
    Johns Hopkins University)

Abstract

Non-covalent interactions of poly(ADP-ribose) (PAR) facilitate condensate formation, yet the impact of these interactions on condensate properties remains unclear. Here, we demonstrate that PAR-mediated interactions through PARP13, specifically the PARP13.2 isoform, are essential for modulating the dynamics of stress granules—a class of cytoplasmic condensates that form upon stress, including types frequently observed in cancers. Single amino acid mutations in PARP13, which reduce its PAR-binding activity, lead to the formation of smaller yet more numerous stress granules than observed in the wild-type. This fragmented stress granule phenotype is also apparent in PARP13 variants with cancer-associated single-nucleotide polymorphisms (SNPs) that disrupt PAR binding. Notably, this fragmented phenotype is conserved across a variety of stresses that trigger stress granule formation via diverse pathways. Furthermore, this PAR-binding mutant diminishes condensate dynamics and impedes fusion. Overall, our study uncovers the important role of PAR-protein interactions in stress granule dynamics and maturation, mediated through PARP13.

Suggested Citation

  • Shang-Jung Cheng & Temitope Gafaar & Jijin R. A. Kuttiyatveetil & Aleksandr Sverzhinsky & Carla Chen & Minghui Xu & Allison Lilley & John M. Pascal & Anthony K. L. Leung, 2025. "Regulation of stress granule maturation and dynamics by poly(ADP-ribose) interaction with PARP13," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55666-0
    DOI: 10.1038/s41467-024-55666-0
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    References listed on IDEAS

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    1. Kengo Watanabe & Kazuhiro Morishita & Xiangyu Zhou & Shigeru Shiizaki & Yasuo Uchiyama & Masato Koike & Isao Naguro & Hidenori Ichijo, 2021. "Cells recognize osmotic stress through liquid–liquid phase separation lubricated with poly(ADP-ribose)," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    2. Shih-Min A. Huang & Yuji M. Mishina & Shanming Liu & Atwood Cheung & Frank Stegmeier & Gregory A. Michaud & Olga Charlat & Elizabeth Wiellette & Yue Zhang & Stephanie Wiessner & Marc Hild & Xiaoying S, 2009. "Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling," Nature, Nature, vol. 461(7264), pages 614-620, October.
    3. Tanya Todorova & Florian J. Bock & Paul Chang, 2014. "PARP13 regulates cellular mRNA post-transcriptionally and functions as a pro-apoptotic factor by destabilizing TRAILR4 transcript," Nature Communications, Nature, vol. 5(1), pages 1-14, December.
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