Human cytomegalovirus long noncoding RNA4.9 regulates viral DNA replication

Tai-Schmiedel, J. et al. (2020) Human cytomegalovirus long noncoding RNA4.9 regulates viral DNA replication. PLoS Pathogens, 16(4), e1008390. (doi: 10.1371/journal.ppat.1008390) (PMID:32294138) (PMCID:PMC7185721)

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Abstract

Viruses are known for their extremely compact genomes composed almost entirely of protein-coding genes. Nonetheless, four long noncoding RNAs (lncRNAs) are encoded by human cytomegalovirus (HCMV). Although these RNAs accumulate to high levels during lytic infection, their functions remain largely unknown. Here, we show that HCMV-encoded lncRNA4.9 localizes to the viral nuclear replication compartment, and that its depletion restricts viral DNA replication and viral growth. RNA4.9 is transcribed from the HCMV origin of replication (oriLyt) and forms an RNA-DNA hybrid (R-loop) through its G+C-rich 5’ end, which may be important for the initiation of viral DNA replication. Furthermore, targeting the RNA4.9 promoter with CRISPR-Cas9 or genetic relocalization of oriLyt leads to reduced levels of the viral single-stranded DNA-binding protein (ssDBP), suggesting that the levels of ssDBP are coupled to the oriLyt activity. We further identified a similar, oriLyt-embedded, G+C-rich lncRNA in murine cytomegalovirus (MCMV). These results indicate that HCMV RNA4.9 plays an important role in regulating viral DNA replication, that the levels of ssDBP are coupled to the oriLyt activity, and that these regulatory features may be conserved among betaherpesviruses.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Suarez, Dr Nicolas and Lau, Dr Betty and Kerr, Mrs Karen and Davison, Professor Andrew
Creator Roles:
Lau, B.Methodology, Resources
Kerr, K.Methodology, Resources
Suárez, N.Data curation, Methodology, Resources
Davison, A. J.Resources, Writing – original draft, Writing – review and editing
Authors: Tai-Schmiedel, J., Karniely, S., Lau, B., Ezra, A., Eliyahu, E., Nachshon, A., Kerr, K., Suárez, N., Schwartz, M., Davison, A. J., and Stern-Ginossar, N.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS Pathogens
Publisher:Public Library of Science
ISSN:1553-7366
ISSN (Online):1553-7374
Published Online:15 April 2020
Copyright Holders:Copyright © 2020 Tai-Schmiedel et al.
First Published:First published in PLoS Pathogens 16(4): e1008390
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
656321Genomics of human cytomegalovirusAndrew DavisonMedical Research Council (MRC)MC_UU_12014/3MVLS III - CENTRE FOR VIRUS RESEARCH