2. Academic Validation
  3. Structural basis for the inhibition of cGAS by nucleosomes

Structural basis for the inhibition of cGAS by nucleosomes

  • Science. 2020 Oct 23;370(6515):455-458. doi: 10.1126/science.abd0237.
Tomoya Kujirai # 1,  Christian Zierhut # 2,  Yoshimasa Takizawa 1,  Ryan Kim 2,  Lumi Negishi 1,  Nobuki Uruma 1 3,  Seiya Hirai 1 4,  Hironori Funabiki 5,  Hitoshi Kurumizaka 6 3 4
Affiliations

Affiliations

  • 1 Laboratory of Chromatin Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
  • 2 Laboratory of Chromosome and Cell Biology, The Rockefeller University, New York, NY 10065, USA.
  • 3 Graduate School of Advanced Science and Engineering, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan.
  • 4 Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
  • 5 Laboratory of Chromosome and Cell Biology, The Rockefeller University, New York, NY 10065, USA. [email protected] [email protected].
  • 6 Laboratory of Chromatin Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. [email protected] [email protected].
  • # Contributed equally.
PMID: 32912999 DOI: 10.1126/science.abd0237
Abstract

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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