DNA-protein cross-links promote cGAS-STING-driven premature aging and embryonic lethality

Area of Science:

• Molecular Biology
• Genetics
• Immunology

Background:

• DNA-protein cross-links (DPCs) are toxic DNA lesions that impede essential cellular processes like replication and transcription.
• The physiological impact of DPCs on a whole organism level remains largely undefined.
• The metalloprotease SPRTN is implicated in DNA repair and genome stability.

Purpose of the Study:

• To investigate the role of SPRTN in preventing DPC-induced pathologies.
• To elucidate the mechanisms by which SPRTN deficiency affects organismal physiology.
• To explore therapeutic strategies targeting DPC-induced immune responses.

Main Methods:

• Utilized a Sprtn knock-in mouse model mimicking Ruijs-Aalfs progeria syndrome.
• Assessed DNA damage, chromosome segregation, micronuclei formation, and cytosolic DNA release.
• Investigated the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway.
• Examined the effects of genetic and pharmacological inhibition of cGAS-STING signaling.

Main Results:

• Loss of SPRTN activity leads to unresolved DNA damage, chromosomal instability, and cytosolic DNA release.
• Cytosolic DNA activates the cGAS-STING innate immune pathway.
• Chronic cGAS-STING signaling in Sprtn-deficient mice causes embryonic lethality due to inflammation.
• Surviving mice exhibit progeroid aging phenotypes starting from embryogenesis.
• Inhibition of cGAS-STING signaling rescues embryonic lethality and alleviates aging phenotypes.

Conclusions:

• SPRTN plays a critical role in suppressing DPC-driven innate immunity and preventing pathological consequences.
• Dysfunctional SPRTN and subsequent chronic cGAS-STING activation contribute to progeroid syndromes.
• Targeting the cGAS-STING pathway offers a potential therapeutic strategy for DPC-related diseases and aging.