Interaction of the Human Papillomavirus E1 Helicase with UAF1-USP1 Promotes Unidirectional Theta Replication of Viral Genomes

ABSTRACT Human papillomaviruses (HPVs) are important pathogens with a significant medical burden. HPV genomes replicate in infected cells via bidirectional theta replication and a poorly understood unidirectional mechanism. In this report, we provide evidence that the previously described interactio...

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Autores principales:	Marit Orav, David Gagnon, Jacques Archambault
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	DNA replication FA pathway human papillomavirus Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/2a52aca3c4454377a9380a59086bb492
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spelling	oai:doaj.org-article:2a52aca3c4454377a9380a59086bb4922021-11-15T15:55:24ZInteraction of the Human Papillomavirus E1 Helicase with UAF1-USP1 Promotes Unidirectional Theta Replication of Viral Genomes10.1128/mBio.00152-192150-7511https://doaj.org/article/2a52aca3c4454377a9380a59086bb4922019-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00152-19https://doaj.org/toc/2150-7511ABSTRACT Human papillomaviruses (HPVs) are important pathogens with a significant medical burden. HPV genomes replicate in infected cells via bidirectional theta replication and a poorly understood unidirectional mechanism. In this report, we provide evidence that the previously described interaction between the viral E1 helicase and the cellular UAF1-USP1 deubiquitinating enzyme complex, a member of the Fanconi anemia DNA damage response pathway, is required for the completion of the bidirectional theta replication of the HPV11 genome and the subsequent initiation of the unidirectional replication. We show that unidirectional replication proceeds via theta structures and is supported by the cellular Bloom helicase, which interacts directly with E1 and whose engagement in HPV11 replication requires UAF1-USP1 activity. We propose that the unidirectional replication of the HPV11 genome initiates from replication fork restart events. These findings suggest a new role for the Fanconi anemia pathway in HPV replication. IMPORTANCE Human papillomaviruses (HPVs) are important pathogens that replicate their double-stranded circular DNA genome in the nucleus of infected cells. HPV genomes replicate in infected cells via bidirectional theta replication and a poorly understood unidirectional mechanism, and the onset of viral replication requires the engagement of cellular DNA damage response pathways. In this study, we showed that the previously described interaction between the viral E1 helicase and the cellular UAF1-USP1 complex is necessary for the completion of bidirectional replication and the subsequent initiation of the unidirectional replication mechanism. Our results suggest HPVs may use the cellular Fanconi anemia DNA damage pathway to achieve the separation of daughter molecules generated by bidirectional theta replication. Additionally, our results indicate that the unidirectional replication of the HPV genome is initiated from restarted bidirectional theta replication forks.Marit OravDavid GagnonJacques ArchambaultAmerican Society for MicrobiologyarticleDNA replicationFA pathwayhuman papillomavirusMicrobiologyQR1-502ENmBio, Vol 10, Iss 2 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	DNA replication FA pathway human papillomavirus Microbiology QR1-502
spellingShingle	DNA replication FA pathway human papillomavirus Microbiology QR1-502 Marit Orav David Gagnon Jacques Archambault Interaction of the Human Papillomavirus E1 Helicase with UAF1-USP1 Promotes Unidirectional Theta Replication of Viral Genomes
description	ABSTRACT Human papillomaviruses (HPVs) are important pathogens with a significant medical burden. HPV genomes replicate in infected cells via bidirectional theta replication and a poorly understood unidirectional mechanism. In this report, we provide evidence that the previously described interaction between the viral E1 helicase and the cellular UAF1-USP1 deubiquitinating enzyme complex, a member of the Fanconi anemia DNA damage response pathway, is required for the completion of the bidirectional theta replication of the HPV11 genome and the subsequent initiation of the unidirectional replication. We show that unidirectional replication proceeds via theta structures and is supported by the cellular Bloom helicase, which interacts directly with E1 and whose engagement in HPV11 replication requires UAF1-USP1 activity. We propose that the unidirectional replication of the HPV11 genome initiates from replication fork restart events. These findings suggest a new role for the Fanconi anemia pathway in HPV replication. IMPORTANCE Human papillomaviruses (HPVs) are important pathogens that replicate their double-stranded circular DNA genome in the nucleus of infected cells. HPV genomes replicate in infected cells via bidirectional theta replication and a poorly understood unidirectional mechanism, and the onset of viral replication requires the engagement of cellular DNA damage response pathways. In this study, we showed that the previously described interaction between the viral E1 helicase and the cellular UAF1-USP1 complex is necessary for the completion of bidirectional replication and the subsequent initiation of the unidirectional replication mechanism. Our results suggest HPVs may use the cellular Fanconi anemia DNA damage pathway to achieve the separation of daughter molecules generated by bidirectional theta replication. Additionally, our results indicate that the unidirectional replication of the HPV genome is initiated from restarted bidirectional theta replication forks.
format	article
author	Marit Orav David Gagnon Jacques Archambault
author_facet	Marit Orav David Gagnon Jacques Archambault
author_sort	Marit Orav
title	Interaction of the Human Papillomavirus E1 Helicase with UAF1-USP1 Promotes Unidirectional Theta Replication of Viral Genomes
title_short	Interaction of the Human Papillomavirus E1 Helicase with UAF1-USP1 Promotes Unidirectional Theta Replication of Viral Genomes
title_full	Interaction of the Human Papillomavirus E1 Helicase with UAF1-USP1 Promotes Unidirectional Theta Replication of Viral Genomes
title_fullStr	Interaction of the Human Papillomavirus E1 Helicase with UAF1-USP1 Promotes Unidirectional Theta Replication of Viral Genomes
title_full_unstemmed	Interaction of the Human Papillomavirus E1 Helicase with UAF1-USP1 Promotes Unidirectional Theta Replication of Viral Genomes
title_sort	interaction of the human papillomavirus e1 helicase with uaf1-usp1 promotes unidirectional theta replication of viral genomes
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/2a52aca3c4454377a9380a59086bb492
work_keys_str_mv	AT maritorav interactionofthehumanpapillomaviruse1helicasewithuaf1usp1promotesunidirectionalthetareplicationofviralgenomes AT davidgagnon interactionofthehumanpapillomaviruse1helicasewithuaf1usp1promotesunidirectionalthetareplicationofviralgenomes AT jacquesarchambault interactionofthehumanpapillomaviruse1helicasewithuaf1usp1promotesunidirectionalthetareplicationofviralgenomes
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Interaction of the Human Papillomavirus E1 Helicase with UAF1-USP1 Promotes Unidirectional Theta Replication of Viral Genomes

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