ATR Safeguards Epithelial-to-Mesenchymal Transition by Countering R-loops and Enabling Transcription Reprogramming.

Area of Science:

• Cancer Biology
• Molecular Oncology
• Genomic Instability

Background:

• Cancer cell plasticity, driven by transcription reprogramming, promotes metastasis and therapeutic resistance.
• Cell-state transitions, such as epithelial-to-mesenchymal transition (EMT), are critical for tumor progression.
• Therapeutic targeting of these transitions remains largely unexplored.

Purpose of the Study:

• To investigate if cell-state transitions can be therapeutically targeted.
• To elucidate the role of ATR kinase in regulating transcription reprogramming during EMT.
• To determine the potential of ATR inhibition as a cancer therapy.

Main Methods:

• Utilized the epithelial-to-mesenchymal transition (EMT) as a model system.
• Investigated the impact of ATR inhibition on genomic instability during EMT.
• Analyzed R-loop formation, transcription-replication conflicts, and gene regulation at the SNAI1 locus.

Main Results:

• Transcription reprogramming during cell-state transitions induces genomic instability via R-loops and transcription-replication conflicts.
• ATR kinase is essential for cell-state transitions, protecting genome integrity and enabling transcription reprogramming.
• ATR inhibition during EMT increases genomic instability, disrupts transcription reprogramming, and elevates R-loop-associated DNA damage at SNAI1.
• ATR inhibition triggers repression of SNAI1 and other EMT genes, reducing tumor growth and metastasis in vivo.

Conclusions:

• ATR kinase safeguards cell-state transitions by maintaining genome integrity and facilitating transcription reprogramming.
• ATR inhibition represents a promising therapeutic strategy to target cancer plasticity and suppress tumor progression.
• Targeting ATR can eliminate cancer cells undergoing EMT, offering a novel approach to combat metastasis and therapeutic resistance.