Structural basis for the inhibition of cGAS by nucleosomes.

Tomoya Kujirai, Christian Zierhut, Yoshimasa Takizawa, Ryan Kim, Lumi Negishi, Nobuki Uruma, Seiya Hirai, Hironori Funabiki, Hitoshi Kurumizaka

Science (New York, N.Y.) 2020 Oct 23

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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. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Citation

Tomoya Kujirai, Christian Zierhut, Yoshimasa Takizawa, Ryan Kim, Lumi Negishi, Nobuki Uruma, Seiya Hirai, Hironori Funabiki, Hitoshi Kurumizaka. Structural basis for the inhibition of cGAS by nucleosomes. Science (New York, N.Y.). 2020 Oct 23;370(6515):455-458