{"doi":"10.64898/2026.05.19.726263","title":"Protein•DNA mesh assembly drives dsDNA-specific and duplex length-dependent activation of cGAS","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>Cyclic G/AMP synthase (cGAS) forms condensates on dysregulated double-stranded (ds) DNA to trigger inflammatory responses. Currently, how it specifically recognizes dsDNA and why activation depends on duplex length remain poorly understood. Using cryo-electron microscopy, biochemical assays, and single-molecule methods, we show that full-length cGAS assembles a protein•dsDNA mesh by reiteratively propagating dimers-of-dimers, driving an associative phase transition. Previously uncharacterized N- and C-terminal interactions, together with inter-dimer junction-loops, track the B-form groove and bend dsDNA to build an extensive mesh network spanning multiple duplexes. These interactions are critical for cross-stabilizing active cGAS, revealing why higher-order assembly on long duplexes maximizes signaling activity. Remarkably, cGAS can build the protein•dsDNA mesh on a single contiguous duplex by entangling its oligomerization platform, resulting in a mechanically resilient and kinetically stable signaling platform. Together, our findings establish higher-order mesh assembly of cGAS as the foundation for dsDNA selectivity, duplex-length-dependent activation, and condensate formation.</jats:p>","journal":null,"year":null,"id":644557,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1677755,"name":"Christina M. Stallings","orcid":null,"position":1,"is_corresponding":false},{"id":1677756,"name":"Stephanie M. Torres","orcid":null,"position":2,"is_corresponding":false},{"id":467620,"name":"Brendan Antiochos","orcid":"0000-0001-6166-9750","position":3,"is_corresponding":false},{"id":278652,"name":"Jungsan Sohn","orcid":"0000-0002-9570-2544","position":4,"is_corresponding":false},{"id":1028410,"name":"Shuai Wu","orcid":"0000-0002-9210-2033","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Protein•DNA mesh assembly drives dsDNA-specific and duplex length-dependent activation of cGAS","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>Cyclic G/AMP synthase (cGAS) forms condensates on dysregulated double-stranded (ds) DNA to trigger inflammatory responses. Currently, how it specifically recognizes dsDNA and why activation depends on duplex length remain poorly understood. Using cryo-electron microscopy, biochemical assays, and single-molecule methods, we show that full-length cGAS assembles a protein•dsDNA mesh by reiteratively propagating dimers-of-dimers, driving an associative phase transition. Previously uncharacterized N- and C-terminal interactions, together with inter-dimer junction-loops, track the B-form groove and bend dsDNA to build an extensive mesh network spanning multiple duplexes. These interactions are critical for cross-stabilizing active cGAS, revealing why higher-order assembly on long duplexes maximizes signaling activity. Remarkably, cGAS can build the protein•dsDNA mesh on a single contiguous duplex by entangling its oligomerization platform, resulting in a mechanically resilient and kinetically stable signaling platform. Together, our findings establish higher-order mesh assembly of cGAS as the foundation for dsDNA selectivity, duplex-length-dependent activation, and condensate formation.</jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":null,"pmcid":null,"openalex_id":null,"authors":[],"funders":[{"funder_name":"NIH","grant_id":"R35 GM145363","title":null},{"funder_name":"NIH","grant_id":"AR085266","title":null},{"funder_name":"","grant_id":"Synergy Award","title":null}],"total_grants":3,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":null,"license":"http://creativecommons.org/licenses/by/4.0/","oa_locations":[{"url":"https://syndication.highwire.org/content/doi/10.64898/2026.05.19.726263","host_type":"publisher"}],"fields_of_study":[],"mesh_terms":[],"keywords":[],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-09T01:31:15.343276Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}