2. Academic Validation
  3. RNA damage compartmentalization by DHX9 stress granules

RNA damage compartmentalization by DHX9 stress granules

  • Cell. 2024 Mar 7:S0092-8674(24)00231-9. doi: 10.1016/j.cell.2024.02.028.
Yilong Zhou 1,  Amol Panhale 1,  Maria Shvedunova 1,  Mirela Balan 1,  Alejandro Gomez-Auli 1,  Herbert Holz 1,  Janine Seyfferth 1,  Martin Helmstädter 2,  Séverine Kayser 2,  Yuling Zhao 3,  Niyazi Umut Erdogdu 3,  Iga Grzadzielewska 3,  Gerhard Mittler 1,  Thomas Manke 1,  Asifa Akhtar 4
Affiliations

Affiliations

  • 1 Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
  • 2 EMcore, Renal Division, Department of Medicine, University Freiburg, Hospital Freiburg, University Faculty of Medicine, Freiburg, Germany.
  • 3 Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany; International Max Planck Research School for Molecular and Cellular Biology (IMPRS-MCB), Freiburg, Germany.
  • 4 Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany. Electronic address: akhtar@ie-freiburg.mpg.de.
PMID: 38503283 DOI: 10.1016/j.cell.2024.02.028
Abstract

Biomolecules incur damage during stress conditions, and damage partitioning represents a vital survival strategy for cells. Here, we identified a distinct stress granule (SG), marked by dsRNA helicase DHX9, which compartmentalizes ultraviolet (UV)-induced RNA, but not DNA, damage. Our FANCI technology revealed that DHX9 SGs are enriched in damaged intron RNA, in contrast to classical SGs that are composed of mature mRNA. UV exposure causes RNA crosslinking damage, impedes intron splicing and decay, and triggers DHX9 SGs within daughter cells. DHX9 SGs promote cell survival and induce dsRNA-related immune response and translation shutdown, differentiating them from classical SGs that assemble downstream of translation arrest. DHX9 modulates dsRNA abundance in the DHX9 SGs and promotes cell viability. Autophagy receptor p62 is activated and important for DHX9 SG disassembly. Our findings establish non-canonical DHX9 SGs as a dedicated non-membrane-bound cytoplasmic compartment that safeguards daughter cells from parental RNA damage.

Keywords

DHX9; DNA damage; RNA damage; autophagy; condensate; mitosis; p62; stress granules.

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