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Activation of DNA Damage Response Pathways during Lytic Replication of KSHV

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of several human malignancies. Human tumour viruses such as KSHV are known to interact with the DNA damage response (DDR), the molecular pathways that recognise and repair lesions in cellular DNA. Here it is demonstrated that lyti...

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Autores principales: Hollingworth, Robert, Skalka, George L., Stewart, Grant S., Hislop, Andrew D., Blackbourn, David J., Grand, Roger J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488719/
https://www.ncbi.nlm.nih.gov/pubmed/26057167
http://dx.doi.org/10.3390/v7062752
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author Hollingworth, Robert
Skalka, George L.
Stewart, Grant S.
Hislop, Andrew D.
Blackbourn, David J.
Grand, Roger J.
author_facet Hollingworth, Robert
Skalka, George L.
Stewart, Grant S.
Hislop, Andrew D.
Blackbourn, David J.
Grand, Roger J.
author_sort Hollingworth, Robert
collection PubMed
description Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of several human malignancies. Human tumour viruses such as KSHV are known to interact with the DNA damage response (DDR), the molecular pathways that recognise and repair lesions in cellular DNA. Here it is demonstrated that lytic reactivation of KSHV leads to activation of the ATM and DNA-PK DDR kinases resulting in phosphorylation of multiple downstream substrates. Inhibition of ATM results in the reduction of overall levels of viral replication while inhibition of DNA-PK increases activation of ATM and leads to earlier viral release. There is no activation of the ATR-CHK1 pathway following lytic replication and CHK1 phosphorylation is inhibited at later times during the lytic cycle. Despite evidence of double-strand breaks and phosphorylation of H2AX, 53BP1 foci are not consistently observed in cells containing lytic virus although RPA32 and MRE11 localise to sites of viral DNA synthesis. Activation of the DDR following KSHV lytic reactivation does not result in a G1 cell cycle block and cells are able to proceed to S-phase during the lytic cycle. KSHV appears then to selectively activate DDR pathways, modulate cell cycle progression and recruit DDR proteins to sites of viral replication during the lytic cycle.
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spelling pubmed-44887192015-07-02 Activation of DNA Damage Response Pathways during Lytic Replication of KSHV Hollingworth, Robert Skalka, George L. Stewart, Grant S. Hislop, Andrew D. Blackbourn, David J. Grand, Roger J. Viruses Article Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of several human malignancies. Human tumour viruses such as KSHV are known to interact with the DNA damage response (DDR), the molecular pathways that recognise and repair lesions in cellular DNA. Here it is demonstrated that lytic reactivation of KSHV leads to activation of the ATM and DNA-PK DDR kinases resulting in phosphorylation of multiple downstream substrates. Inhibition of ATM results in the reduction of overall levels of viral replication while inhibition of DNA-PK increases activation of ATM and leads to earlier viral release. There is no activation of the ATR-CHK1 pathway following lytic replication and CHK1 phosphorylation is inhibited at later times during the lytic cycle. Despite evidence of double-strand breaks and phosphorylation of H2AX, 53BP1 foci are not consistently observed in cells containing lytic virus although RPA32 and MRE11 localise to sites of viral DNA synthesis. Activation of the DDR following KSHV lytic reactivation does not result in a G1 cell cycle block and cells are able to proceed to S-phase during the lytic cycle. KSHV appears then to selectively activate DDR pathways, modulate cell cycle progression and recruit DDR proteins to sites of viral replication during the lytic cycle. MDPI 2015-06-05 /pmc/articles/PMC4488719/ /pubmed/26057167 http://dx.doi.org/10.3390/v7062752 Text en © 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hollingworth, Robert
Skalka, George L.
Stewart, Grant S.
Hislop, Andrew D.
Blackbourn, David J.
Grand, Roger J.
Activation of DNA Damage Response Pathways during Lytic Replication of KSHV
title Activation of DNA Damage Response Pathways during Lytic Replication of KSHV
title_full Activation of DNA Damage Response Pathways during Lytic Replication of KSHV
title_fullStr Activation of DNA Damage Response Pathways during Lytic Replication of KSHV
title_full_unstemmed Activation of DNA Damage Response Pathways during Lytic Replication of KSHV
title_short Activation of DNA Damage Response Pathways during Lytic Replication of KSHV
title_sort activation of dna damage response pathways during lytic replication of kshv
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488719/
https://www.ncbi.nlm.nih.gov/pubmed/26057167
http://dx.doi.org/10.3390/v7062752
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