Dysfunctional telomeres trigger cellular senescence mediated by cyclic GMP-AMP synthase.

Area of Science:

• Cell Biology
• Immunology
• Genetics

Background:

• Defective DNA damage response (DDR) signaling is a known driver of cellular senescence.
• The precise mechanisms linking dysfunctional telomeres to DDR and senescence remain incompletely understood.

Purpose of the Study:

• To elucidate the molecular links between dysfunctional telomeres, DDR, and premature cellular senescence.
• To investigate the role of cytosolic DNA sensing pathways in telomere-induced senescence.

Main Methods:

• CRISPR/Cas9-mediated induction of telomere double-strand breaks.
• Biochemical and imaging techniques including ChIP, telomere immunofluorescence, FISH, and TeSLA.
• Analysis of cytosolic chromatin fragments and cGAS-STING pathway activation.

Main Results:

• Dysfunctional telomeres induce chromosome mis-segregation, leading to cytosolic chromatin fragments.
• Cyclic GMP-AMP synthase (cGAS) recognizes these fragments, activating the STING pathway and interferon signaling.
• This cGAS-STING activation drives premature cellular senescence independently of telomere shortening.

Conclusions:

• Premature cellular senescence can be initiated by dysfunctional telomeres through a cGAS-mediated cytosolic DNA-sensing pathway.
• This mechanism operates independently of telomere shortening and involves immune signaling activation.
• Targeting the cGAS pathway offers a potential strategy to prevent telomere-induced senescence.