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Evaluation of Caspase Activation to Assess Innate Immune Cell Death
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eccDNAs are apoptotic products with high innate immunostimulatory activity
Yuangao Wang1,2, Meng Wang1,2, Mohamed Nadhir Djekidel1,2
1Howard Hughes Medical Institute, Boston, MA, USA.
Nature
|October 21, 2021
Summary
Extrachromosomal circular DNA elements (eccDNAs) are generated through random DNA fragment ligation during apoptosis. These circular DNA molecules act as potent innate immunostimulants, activating the Sting pathway.
Area of Science:
- Molecular Biology
- Immunology
- Genetics
Background:
- Extrachromosomal circular DNA elements (eccDNAs) are widespread across species but their origins and functions remain largely unknown.
- Previous research has not fully elucidated the mechanisms behind eccDNA biogenesis or their biological roles.
Purpose of the Study:
- To investigate the biogenesis and functions of extrachromosomal circular DNA elements (eccDNAs).
- To characterize the role of eccDNAs in innate immune response and identify their sensing pathways.
Main Methods:
- Development of a novel circular DNA enrichment technique.
- Nanopore sequencing for purification and analysis of full-length eccDNAs.
- Induction of apoptosis and assessment of eccDNA generation and ligation.
Main Results:
- eccDNAs originate from random ligation of genomic DNA fragments, with increased generation during apoptosis.
- Apoptosis-induced eccDNA formation is dependent on DNA fragmentation and DNA ligase 3 activity.
- eccDNAs function as innate immunostimulants, dependent on circularity and the cytosolic DNA sensor Sting, independent of sequence.
Conclusions:
- The study reveals a novel mechanism for eccDNA biogenesis linked to apoptosis.
- eccDNAs are identified as key innate immune stimulants activating the Sting pathway.
- Findings highlight potential clinical implications of eccDNAs in modulating immune responses.
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