TY - JOUR
T1 - Kaposi's sarcoma herpesvirus exploits the DNA damage response to circularize its genome
AU - Li, Shijun
AU - Liu, Bing
AU - Tan, Min
AU - Juillard, Franceline
AU - Szymula, Agnieszka
AU - Álvarez, Ángel L.
AU - Sciver, Nicholas Van
AU - George, Athira
AU - Ramachandran, Akshaya
AU - Raina, Komal
AU - Tumuluri, Vinayak Sadasivam
AU - Costa, Catarina N.
AU - Simas, J. Pedro
AU - Kaye, Kenneth M.
N1 - Publisher Copyright:
© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.
PY - 2024/2/28
Y1 - 2024/2/28
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85186412645&partnerID=8YFLogxK
U2 - 10.1093/nar/gkad1224
DO - 10.1093/nar/gkad1224
M3 - Article
C2 - 38180827
SN - 0305-1048
VL - 52
SP - 1814
EP - 1829
JO - Nucleic Acids Research
JF - Nucleic Acids Research
IS - 4
ER -