Structural basis for the inhibition of cGAS by nucleosomes.
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Date
2020-10-23ICR Author
Author
Kujirai, T
Zierhut, C
Takizawa, Y
Kim, R
Negishi, L
Uruma, N
Hirai, S
Funabiki, H
Kurumizaka, H
Type
Journal Article
Metadata
Show full item recordAbstract
The cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) senses invasion of pathogenic DNA and stimulates inflammatory signaling, autophagy, and apoptosis. Organization of host DNA into nucleosomes was proposed to limit cGAS autoinduction, but the underlying mechanism was unknown. Here, we report the structural basis for this inhibition. In the cryo-electron microscopy structure of the human cGAS-nucleosome core particle (NCP) complex, two cGAS monomers bridge two NCPs by binding the acidic patch of the histone H2A-H2B dimer and nucleosomal DNA. In this configuration, all three known cGAS DNA binding sites, required for cGAS activation, are repurposed or become inaccessible, and cGAS dimerization, another prerequisite for activation, is inhibited. Mutating key residues linking cGAS and the acidic patch alleviates nucleosomal inhibition. This study establishes a structural framework for why cGAS is silenced on chromatinized self-DNA.
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Subject
Nucleosomes
Animals
Xenopus
Humans
Nucleotidyltransferases
Nuclear Proteins
DNA
Cryoelectron Microscopy
Catalytic Domain
Protein Conformation
Research team
Epigenetics and Genome Stability
Language
eng
Date accepted
2020-08-28
License start date
2020-10
Citation
Science (New York, N.Y.), 2020, 370 (6515), pp. 455 - 458
Publisher
AMER ASSOC ADVANCEMENT SCIENCE