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dc.contributor.authorKujirai, T
dc.contributor.authorZierhut, C
dc.contributor.authorTakizawa, Y
dc.contributor.authorKim, R
dc.contributor.authorNegishi, L
dc.contributor.authorUruma, N
dc.contributor.authorHirai, S
dc.contributor.authorFunabiki, H
dc.contributor.authorKurumizaka, H
dc.date.accessioned2020-11-10T09:33:14Z
dc.date.issued2020-10
dc.identifier.citationScience (New York, N.Y.), 2020, 370 (6515), pp. 455 - 458
dc.identifier.issn0036-8075
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4218
dc.identifier.eissn1095-9203
dc.identifier.doi10.1126/science.abd0237
dc.description.abstractThe 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.
dc.formatPrint-Electronic
dc.format.extent455 - 458
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved
dc.subjectNucleosomes
dc.subjectAnimals
dc.subjectXenopus
dc.subjectHumans
dc.subjectNucleotidyltransferases
dc.subjectNuclear Proteins
dc.subjectDNA
dc.subjectCryoelectron Microscopy
dc.subjectCatalytic Domain
dc.subjectProtein Conformation
dc.titleStructural basis for the inhibition of cGAS by nucleosomes.
dc.typeJournal Article
dcterms.dateAccepted2020-08-28
rioxxterms.versionofrecord10.1126/science.abd0237
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2020-10
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfScience (New York, N.Y.)
pubs.issue6515
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Epigenetics and Genome Stability
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Epigenetics and Genome Stability
pubs.publication-statusPublished
pubs.volume370
pubs.embargo.termsNot known
icr.researchteamEpigenetics and Genome Stabilityen_US
dc.contributor.icrauthorZierhut, Christianen


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