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

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

doi:10.1093/nar/gkad1224

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

Journal Article · Fri Jan 05 00:00:00 EST 2024 · Nucleic Acids Research

DOI:https://doi.org/10.1093/nar/gkad1224· OSTI ID:2278872

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

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.

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Sponsoring Organization:: USDOE Office of Nuclear Energy (NE), Nuclear Fuel Cycle and Supply Chain

OSTI ID:: 2278872

Journal Information:: Nucleic Acids Research, Journal Name: Nucleic Acids Research Journal Issue: 4 Vol. 52; ISSN 0305-1048

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United Kingdom

Language:: English

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