STING causes replication stress and nascent DNA degradation via SAMHD1

Area of Science:

• Cell Biology
• Immunology
• Genetics

Background:

• STING (stimulator of interferon genes) is crucial for innate immunity, typically activated by cytosolic DNA.
• Its nuclear functions and non-canonical roles, especially in premature aging diseases like Hutchinson Gilford Progeria Syndrome (HGPS), are poorly understood.
• In HGPS, nuclear STING accumulation correlates with chronic inflammation.

Purpose of the Study:

• To investigate the role of nuclear STING in replication stress (RS).
• To elucidate the mechanisms by which nuclear STING impacts DNA replication.
• To identify therapeutic targets for conditions with elevated STING activity.

Main Methods:

• Utilized progeria and tumor cell models.
• Investigated STING localization and chromatin binding under replication stress.
• Assessed the impact of STING on replication fork dynamics and DNA integrity.
• Employed gene knockdown (SAMHD1) to study pathway dependencies.

Main Results:

• Replication stress triggers STING nuclear accumulation and chromatin binding.
• Nuclear STING promotes replication stress by limiting dNTP availability and hindering fork protection.
• STING facilitates MRE11-mediated nascent DNA degradation via SAMHD1.
• SAMHD1 is essential for STING's detrimental effects on DNA replication.

Conclusions:

• A pathological STING-SAMHD1 axis drives replication stress and genome instability in progeria and tumor cells.
• Nuclear STING plays a novel role in promoting replication stress and DNA degradation.
• Targeting the STING-SAMHD1 interaction may offer therapeutic strategies for related diseases.