Kaposi's sarcoma herpesvirus exploits the DNA damage response to circularize its genome
Autor(a) principal: | |
---|---|
Data de Publicação: | 2024 |
Outros Autores: | , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.14/43716 |
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. |
id |
RCAP_04e7deab8e866b364519ae5088db5d14 |
---|---|
oai_identifier_str |
oai:repositorio.ucp.pt:10400.14/43716 |
network_acronym_str |
RCAP |
network_name_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository_id_str |
7160 |
spelling |
Kaposi's sarcoma herpesvirus exploits the DNA damage response to circularize its genomeTo 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.Veritati - Repositório Institucional da Universidade Católica PortuguesaLi, ShijunLiu, BingTan, MinJuillard, FrancelineSzymula, AgnieszkaÁlvarez, Ángel L.Sciver, Nicholas VanGeorge, AthiraRamachandran, AkshayaRaina, KomalTumuluri, Vinayak SadasivamCosta, Catarina N.Simas, J. PedroKaye, Kenneth M.2024-01-24T13:55:45Z20242024-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.14/43716eng0305-104810.1093/nar/gkad122438180827001137014100001info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-02-06T01:37:23Zoai:repositorio.ucp.pt:10400.14/43716Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T01:58:49.804886Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Kaposi's sarcoma herpesvirus exploits the DNA damage response to circularize its genome |
title |
Kaposi's sarcoma herpesvirus exploits the DNA damage response to circularize its genome |
spellingShingle |
Kaposi's sarcoma herpesvirus exploits the DNA damage response to circularize its genome Li, Shijun |
title_short |
Kaposi's sarcoma herpesvirus exploits the DNA damage response to circularize its genome |
title_full |
Kaposi's sarcoma herpesvirus exploits the DNA damage response to circularize its genome |
title_fullStr |
Kaposi's sarcoma herpesvirus exploits the DNA damage response to circularize its genome |
title_full_unstemmed |
Kaposi's sarcoma herpesvirus exploits the DNA damage response to circularize its genome |
title_sort |
Kaposi's sarcoma herpesvirus exploits the DNA damage response to circularize its genome |
author |
Li, Shijun |
author_facet |
Li, Shijun Liu, Bing Tan, Min Juillard, Franceline Szymula, Agnieszka Álvarez, Ángel L. Sciver, Nicholas Van George, Athira Ramachandran, Akshaya Raina, Komal Tumuluri, Vinayak Sadasivam Costa, Catarina N. Simas, J. Pedro Kaye, Kenneth M. |
author_role |
author |
author2 |
Liu, Bing Tan, Min Juillard, Franceline Szymula, Agnieszka Álvarez, Ángel L. Sciver, Nicholas Van George, Athira Ramachandran, Akshaya Raina, Komal Tumuluri, Vinayak Sadasivam Costa, Catarina N. Simas, J. Pedro Kaye, Kenneth M. |
author2_role |
author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Veritati - Repositório Institucional da Universidade Católica Portuguesa |
dc.contributor.author.fl_str_mv |
Li, Shijun Liu, Bing Tan, Min Juillard, Franceline Szymula, Agnieszka Álvarez, Ángel L. Sciver, Nicholas Van George, Athira Ramachandran, Akshaya Raina, Komal Tumuluri, Vinayak Sadasivam Costa, Catarina N. Simas, J. Pedro Kaye, Kenneth M. |
description |
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. |
publishDate |
2024 |
dc.date.none.fl_str_mv |
2024-01-24T13:55:45Z 2024 2024-01-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.14/43716 |
url |
http://hdl.handle.net/10400.14/43716 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
0305-1048 10.1093/nar/gkad1224 38180827 001137014100001 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
|
_version_ |
1799137072667164672 |