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

Shijun Li, Bing Liu, Min Tan, Franceline Juillard, Agnieszka Szymula, Ángel L. Álvarez, Nicholas Van Sciver, Athira George, Akshaya Ramachandran, Komal Raina, Vinayak Sadasivam Tumuluri, Catarina N. Costa, J. Pedro Simas, Kenneth M. Kaye

Resultado de pesquisarevisão de pares

1 Citação (Scopus)
17 Transferências (Pure)

Resumo

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.
Idioma originalEnglish
Páginas (de-até)1814-1829
Número de páginas16
RevistaNucleic Acids Research
Volume52
Número de emissão4
DOIs
Estado da publicaçãoPublicado - 28 fev. 2024

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