ATM counteracts chromatin-bound cGAS during DNA replication

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Cyclic GMP-AMP synthase (cGAS) is a DNA sensor that initiates type-I interferon responses.
• cGAS is normally sequestered in the nucleus via chromatin binding, but its role in DNA metabolism is unclear.

Purpose of the Study:

• To investigate the impact of chromatin-bound cGAS on DNA replication and cellular responses.
• To elucidate the regulatory mechanisms controlling cGAS chromatin association and its functional consequences.

Main Methods:

• Utilized cell-based assays to assess DNA replication fork dynamics and DNA fragmentation.
• Employed genetic manipulation (ATM/ATR inhibition, cGAS depletion) to dissect regulatory pathways.
• Investigated protein-protein interactions and phosphorylation events.

Main Results:

• Chromatin-bound cGAS impedes DNA replication forks, causing fork slowing and nascent DNA fragmentation.
• ATM kinase, supported by ATR, phosphorylates MRE11 to release cGAS from chromatin, thereby tolerating its nuclear presence.
• ATM deficiency leads to replication stress, cytosolic cGAS activation, and synthetic lethality upon ATR inhibition, particularly in cancer cells.

Conclusions:

• ATM and chromatin-bound cGAS form a regulatory circuit essential for maintaining replication homeostasis and controlling cGAS signaling in proliferating cells.
• cGAS emerges as a potential biomarker for predicting sensitivity to ATR inhibitor therapy in ATM-deficient cancers.
• Understanding this interplay is crucial for developing targeted cancer therapies and managing immune responses.