Structural basis of nucleosome-dependent cGAS inhibition
Open accessAbstract
Saving a host cell from itself: A fundamental mammalian defense mechanism against pathogens and damaged cellular DNA is to recognize DNA fragments in the cytosol and trigger an inflammatory response. The cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) that recognizes cytosolic DNA is also found in the nucleus, but here its activity is suppressed by tethering to chromatin. Two papers now report cryo–electron microscopy structures of cGAS bound to the nucleosome core particle (NCP). Kujirai et al. observed a structure with two cGAS molecules bridging two NCPs, whereas Boyer et al. observed cGAS bound to a single nucleosome. Together, these structures show how cGAS is prevented from autoreactivity toward host DNA. Science , this issue p. 455 , p. 450
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cGAS is suppressed by binding to nucleosomes and disruption of nucleosome regulation enables robust DNA-dependent activation of cGAS.
“Previously, we and others showed that cGAS is suppressed by binding to nucleosomes and that disruption of nucleosome regulation enables robust DNA-dependent activation of cGAS32–37 (Fig. 4a).”
From cGAS–STING drives ageing-related inflammation and neurodegeneration (2023) · cites this paper as [36]
cGAS is inhibited by nucleosome binding.
“inhibition by nucleosome binding (Boyer et al., 2020; Kujirai et al., 2020; Michalski et al., 2020; Pathare et al., 2020; Zhao et al., 2020b)”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Boyer et al., 2020
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References 44 · Cited by 238
- Authors
- Boyer, J. A., Spangler, C. J., Strauss, J. D., Cesmat, A. P., Liu, P., McGinty, R. K., & Zhang, Q.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Boyer, Joshua A.
- Spangler, Cathy J.
- Strauss, Joshua D.
- McGinty, Robert K.
- Zhang, Qi
- Venue
- Science
- Published
- 2020-10-23
- Volume
- 370
- Issue
- 6515
- Pages
- 450-454
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC8189757
- OpenAlex
- W3086888894
- Cited by
- 238
- References
- 44
- Citations by year
- 2026: 35 · 2025: 36 · 2024: 38 · 2023: 29 · 2022: 32 · 2021: 58 · 2020: 9 · 2013: 1
- FWCI
- 11.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Cancer Institute (R21CA234979, F99CA253730)
- National Institute of General Medical Sciences (1R35GM133498)
- Pew Charitable Trusts
- School of Medicine, University of North Carolina at Chapel Hill
- Searle Scholars Program
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- cGAS, nucleosome, nucleosome core particle, chromatin tethering, innate immunity, nucleosome acidic patch, arginine binding, protein-DNA interactions, double-stranded DNA binding, cryo-EM structure
- MeSH terms
- Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, DNA, Humans, Nuclear Proteins, Nucleosomes, Nucleotidyltransferases, Catalytic Domain, Cryoelectron Microscopy, Protein Multimerization
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