A PRMT5-ZNF326 axis mediates innate immune activation upon replication stress

Area of Science:

• Molecular Biology
• Cancer Research
• Immunology

Background:

• DNA replication stress (RS) is a hallmark of cancer, leading to genomic instability and chromatin changes.
• DNA damage triggers innate immune signaling, but the regulators involved in replication stress responses are poorly understood.

Purpose of the Study:

• To identify transcriptional regulators mediating innate immune signaling during DNA replication stress.
• To elucidate the role of protein arginine methyltransferase 5 (PRMT5) in replication stress-induced gene expression.

Main Methods:

• Chemical screening to identify key mediators of replication stress response.
• Quantitative mass spectrometry to identify proteins with symmetric dimethylarginine (SDMA) modifications.
• Functional assays to assess the role of PRMT5 and ZNF326 in interferon-stimulated gene (ISG) induction.

Main Results:

• PRMT5 was identified as a crucial mediator of RS-dependent induction of interferon-stimulated genes (ISGs).
• RS induces PRMT5-dependent symmetric dimethylarginine (SDMA) modifications on specific proteins.
• PRMT5 directly targets and modulates the activity of ZNF326, a key factor in ISG response.

Conclusions:

• PRMT5-mediated SDMA plays a significant role in transcriptional induction during replication stress.
• This pathway impacts physiological homeostasis and has implications for cancer therapy.
• PRMT5 is a potential therapeutic target for managing replication stress in cancer.