Human cytomegalovirus long noncoding RNA4.9 regulates viral DNA replication

Julie Tai-Schmiedel, Sharon Karniely, Betty Lau, Adi Ezra, Erez Eliyahu, Aharon Nachshon, Karen Kerr, Nicolás Suárez, Michal Schwartz, Andrew J. Davison, Noam Stern-Ginossar

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

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.

Original languageEnglish
Article numbere1008390
JournalPLoS Pathogens
Volume16
Issue number4
DOIs
StatePublished - 1 Apr 2020
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2020 Tai-Schmiedel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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