Nuclear retention and RNA editing safeguard self-tolerance to immunogenic intron lariats

In breast cancer cells with high intron-lariat burden, DBR1 inhibition reveals IRAlus-containing lariats that trigger cell cycle–dependent PKR activation, nuclear retention, and apoptosis.

• Why it matters: Intron lariats are normally degraded after splicing, leaving how they might regulate immunity unclear, especially for repeat-rich introns that could otherwise become self-reactive.
• What they did: The study mapped the intron lariat landscape under DBR1 inhibition, then tested how cytosolic release and A-to-I editing of IRAlus-containing lariats affect PKR activation and cell fate.
• The result: Cytosolic release of immunogenic lariats drives PKR activation and apoptosis, while A-to-I editing weakens lariat–PKR interactions; combining DBR1 depletion with anti-mitotic chemotherapy enhances cancer cell death in vitro and in vivo.

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