The DNA damage response induces IFN.

Area of Science:

• Cellular Biology
• Immunology
• Genetics

Background:

• The DNA damage response (DDR) is critical for maintaining genomic stability.
• Innate immune signaling, particularly interferon (IFN) pathways, is typically associated with viral infections.
• The interplay between DDR and innate immunity was not well understood.

Purpose of the Study:

• To investigate the potential link between DNA damage and the activation of IFN signaling pathways.
• To elucidate the molecular mechanisms connecting DNA damage to IFN gene induction.

Main Methods:

• Human cells were treated with etoposide to induce double-stranded DNA breaks.
• Gene expression analysis was performed to assess IFN-stimulated genes, IFN-α, and IFN-λ.
• The role of NF-κB and its subunits (p65/RelA) in regulating IFN gene induction was examined.
• Studies involved cells with and without the NF-κB essential modulator.

Main Results:

• Etoposide treatment induced IFN-stimulated genes, IFN-α, and IFN-λ.
• NF-κB was identified as a key regulator for IFN gene induction following DNA damage.
• Expression of NF-κB subunit p65/RelA alone induced the IFN-λ1 gene.
• NF-κB was essential for inducing IFN regulatory factors (IRFs) -1 and -7, which further drive IFN-α and IFN-λ expression.
• Cells lacking the NF-κB essential modulator could not induce IFN genes after DNA damage.

Conclusions:

• DNA damage activates IFN signaling, representing a novel cellular stress response.
• NF-κB plays a pivotal role in mediating the induction of IFN genes in response to DNA damage.
• This finding broadens the understanding of IFN signaling roles beyond viral defense, linking it to genomic integrity maintenance.