An inducible long noncoding RNA amplifies DNA damage signaling

Area of Science:

• Molecular Biology
• Genetics
• Cellular Biology

Background:

• Long noncoding RNAs (lncRNAs) are a significant class of genes with largely uncharacterized functions.
• The precise regulatory roles of lncRNAs in cellular processes, particularly in response to stress, remain largely unknown.
• Understanding the involvement of lncRNAs in DNA damage pathways is crucial for deciphering cellular defense mechanisms.

Purpose of the Study:

• To investigate the role of lncRNAs in guiding the organismal DNA damage response.
• To elucidate the mechanism by which lncRNAs interact with key regulatory proteins in DNA damage signaling.
• To determine the therapeutic potential of targeting lncRNAs in conditions associated with DNA damage.

Main Methods:

• Utilized p53-dependent transcription activation assays to identify lncRNAs induced by DNA damage.
• Employed gene knockout and promoter inactivation models in mice to assess the in vivo function of the identified lncRNA.
• Performed protein-binding assays to confirm the interaction between the lncRNA and p53.
• Analyzed gene expression, cell cycle progression, and apoptosis markers in response to DNA damage and lncRNA modulation.

Main Results:

• Discovered that DNA damage induces the transcription of the DINO (Damage Induced Noncoding) lncRNA via p53.
• Demonstrated that DINO is essential for p53-dependent gene expression, cell cycle arrest, and apoptosis following DNA damage.
• Showed that DINO expression alone can trigger DNA damage signaling and cell cycle arrest.
• Confirmed that DINO binds to p53, enhancing its stability and creating a positive feedback loop.
• Observed that Dino knockout or promoter inactivation in mice attenuated p53 signaling and mitigated acute radiation syndrome.

Conclusions:

• lncRNAs, exemplified by DINO, play a critical role in orchestrating the cellular DNA damage response.
• The inducible DINO lncRNA forms a feedback loop with p53, amplifying cellular signaling pathways.
• Targeting lncRNA-protein interactions presents a potential therapeutic strategy for radiation-induced injuries and other DNA damage-related conditions.