{"doi":"10.1093/nar/gkad1224","title":"Kaposi's sarcoma herpesvirus exploits the DNA damage response to circularize its genome","abstract":"To establish lifelong, latent infection, herpesviruses circularize their linear, double-stranded, DNA genomes through an unknown mechanism. Kaposi's sarcoma (KS) herpesvirus (KSHV), a gamma herpesvirus, is tightly linked with KS, primary effusion lymphoma, and multicentric Castleman's disease. KSHV persists in latently infected cells as a multi-copy, extrachromosomal episome. Here, we show the KSHV genome rapidly circularizes following infection, and viral protein expression is unnecessary for this process. The DNA damage response (DDR) kinases, ATM and DNA-PKcs, each exert roles, and absence of both severely compromises circularization and latency. These deficiencies were rescued by expression of ATM and DNA-PKcs, but not catalytically inactive mutants. In contrast, γH2AX did not function in KSHV circularization. The linear viral genomic ends resemble a DNA double strand break, and non-homologous DNA end joining (NHEJ) and homologous recombination (HR) reporters indicate both NHEJ and HR contribute to KSHV circularization. Last, we show, similar to KSHV, ATM and DNA-PKcs have roles in circularization of the alpha herpesvirus, herpes simplex virus-1 (HSV-1), while γH2AX does not. Therefore, the DDR mediates KSHV and HSV-1 circularization. This strategy may serve as a general herpesvirus mechanism to initiate latency, and its disruption may provide new opportunities for prevention of herpesvirus disease.","journal":"Nucleic Acids Research","year":2024,"id":455122,"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":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.961,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":692418,"name":"Bing Liu","orcid":"0000-0002-7313-6924","position":1,"is_corresponding":false},{"id":728240,"name":"Min Tan","orcid":"0000-0003-1719-7359","position":2,"is_corresponding":false},{"id":728242,"name":"Franceline Juillard","orcid":"0000-0003-1449-3603","position":3,"is_corresponding":false},{"id":729091,"name":"Agnieszka Szymula","orcid":null,"position":4,"is_corresponding":false},{"id":728246,"name":"Ángel L. Álvarez","orcid":"0000-0001-9388-8595","position":5,"is_corresponding":false},{"id":488613,"name":"Nicholas Van Sciver","orcid":"0000-0001-7967-6895","position":6,"is_corresponding":false},{"id":1080464,"name":"Athira George","orcid":null,"position":7,"is_corresponding":false},{"id":428658,"name":"Akshaya Ramachandran","orcid":"0000-0002-8727-2046","position":8,"is_corresponding":false},{"id":689393,"name":"Komal Raina","orcid":"0000-0003-0371-1070","position":9,"is_corresponding":false},{"id":1278957,"name":"Vinayak Sadasivam Tumuluri","orcid":"0000-0003-3668-2122","position":10,"is_corresponding":false},{"id":1278958,"name":"Catarina Costa","orcid":"0000-0002-0764-3215","position":11,"is_corresponding":false},{"id":728248,"name":"J. Pedro Simas","orcid":"0000-0001-6982-9253","position":12,"is_corresponding":false},{"id":728250,"name":"Kenneth M. Kaye","orcid":"0000-0001-5802-4556","position":13,"is_corresponding":false},{"id":728241,"name":"Shijun Li","orcid":"0000-0002-3622-9435","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":null,"created_at":"2026-07-19T02:03:17.458329Z","pmid":"38180827","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":[]}