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Kaposi's sarcoma herpesvirus exploits the DNA damage response to circularize its genome

2024Journal article Open access
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dc.contributor.authorLi, Shijun
dc.contributor.authorLiu, Bing
dc.contributor.authorTan, Min
dc.contributor.authorJuillard, Franceline
dc.contributor.authorSzymula, Agnieszka
dc.contributor.authorÁlvarez, Ángel L.
dc.contributor.authorSciver, Nicholas Van
dc.contributor.authorGeorge, Athira
dc.contributor.authorRamachandran, Akshaya
dc.contributor.authorRaina, Komal
dc.contributor.authorTumuluri, Vinayak Sadasivam
dc.contributor.authorCosta, Catarina N.
dc.contributor.authorSimas, J. Pedro
dc.contributor.authorKaye, Kenneth M.
dc.date.accessioned2024-01-24T13:55:45Z
dc.date.available2024-01-24T13:55:45Z
dc.date.issued2024
dc.description.abstractTo 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.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.1093/nar/gkad1224pt_PT
dc.identifier.eid85186412645
dc.identifier.issn0305-1048
dc.identifier.pmcPMC10899755
dc.identifier.pmid38180827
dc.identifier.urihttp://hdl.handle.net/10400.14/43716
dc.identifier.wos001137014100001
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/pt_PT
dc.titleKaposi's sarcoma herpesvirus exploits the DNA damage response to circularize its genomept_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.titleNucleic Acids Researchpt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT

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